Weight and body composition changes during and after adjuvant chemotherapy in women with breast cancer.

Uncontrolled trials have reported significant weight gain in women with breast cancer during treatment with adjuvant chemotherapy. We prospectively evaluated body composition before (visit 1), immediately after (visit 2), and 6 months after (visit 3) chemotherapy in 20 women with stages I-IIIA breast cancer [body mass index (BMI): 24.1 +/- 3.9 kg/m(2)]. We compared their weight change to 51 age- and BMI-matched healthy controls (BMI: 25.5 +/- 3.8 kg/m(2)). In women with breast cancer, there was no weight change from visit 1-2, or from visit 1-3, but weight increased from visit 2-3 (+1.09 +/- 2.46 kg; P = 0.05). Weight change was not different from controls during either interval. In the breast cancer group, the percentage of body fat assessed by air displacement plethysmography increased, and fat-free mass decreased from visit 1-2 (+2.3 +/- 4% and -2.2 +/- 4%; P = 0.02) and from visit 1-3 (+4.0 +/- 6% and -3.8 +/- 6%; P = 0.01). By dual energy x-ray absorptiometry, the percentage of body fat increased from visit 2-3 (+0.9 +/- 1.6%; P = 0.02). Bone mineral content decreased from visit 2-3 (-0.02 +/- 0.04 kg; P = 0.02) and from visit 1-3 (-0.04 +/- 0.06 kg; P = 0.005). By computed tomography, the visceral adipose to sc adipose tissue ratio decreased from visit 1-3 (-0.02 +/- 0.05 ml; P = 0.02). We conclude that, compared with controls, women with breast cancer receiving modern adjuvant chemotherapy regimens show no significant changes in weight during the first year of their treatment. They do, however, appear to undergo unfavorable changes in body composition.

In vivo effects of a potent GnRH antagonist ORG 30850: physiologic evidence that down-regulation of GnRH receptors does not occur.

OBJECTIVE: Our purpose was to determine the pituitary responsiveness to exogenous GnRH in GnRH antagonist-suppressed ovariectomized monkeys. METHODS: This was a prospective experimental non-human primate study performed at the research laboratories of The Jones Institute for Reproductive Medicine. Seventeen long-term ovariectomized cynomolgus monkeys were studied. INTERVENTIONS: The GnRH antagonist ORG 30850 was administered to long-term ovariectomized monkeys assigned to one of six groups: single subcutaneous injections in group A (n = 4), 0.3 mg/kg; group B (n = 4), 1.0 mg/kg; and group C (n = 3), 3.0 mg/kg; and six consecutive daily subcutaneous injections in group D (n = 2), 0.3 mg/kg; group E (n = 2), 1.0 mg/kg; and group F (n = 2), 3.0 mg/kg. Blood samples were collected daily from 10 days before treatment until 22 days after treatment, then weekly for 6 additional weeks. Intravenous GnRH stimulation tests (10 micrograms/kg) were performed on the day after vehicle injection (control) and the day after completion of treatment(s), and then at weekly intervals. The main outcome measures were serum levels of LH, FSH, and ORG 30850. RESULTS: Administration of ORG 30850 resulted in suppression (P < .05) of LH and FSH in all treatment groups. Long-term suppression (greater than 2 weeks) was evident in all primates receiving a cumulative dose of at least 1 mg/kg. Paradoxically, the responsiveness of the pituitary to exogenous GnRH was accentuated during the time of maximal tonic LH/FSH suppression. CONCLUSIONS: ORG 30850 is a potent long-acting GnRH antagonist. Furthermore, the present in vivo demonstration of heightened pituitary responsiveness to exogenous GnRH emphasizes the divergent mechanisms of action of GnRH antagonists and GnRH agonists.

Effect of hypnotic suggestion on the delayed-type hypersensitivity response.

OBJECTIVE: To determine whether individuals selected for good general health, high hypnotizability, and the ability to alter skin temperature under hypnotic suggestion can influence the delayed-type hypersensitivity (DTH) response to varicella-zoster (VZ) antigen under hypnotic suggestion. DESIGN: A blinded clinical trial using a repeated measures design with subjects serving as their own controls. Subjects were randomly assigned to undergo a predetermined sequence of four different experimental conditions, occurring at weekly intervals, with each condition including VZ skin testing: (1) hypnosis with suggestions to enhance the DTH response to VZ antigen; (2) hypnosis with suggestions to suppress the DTH response; (3) hypnosis with suggestions for relaxation only; and (4) skin testing without hypnosis. SETTING: A National Institutes of Health-supported clinical research center in a teaching hospital. SUBJECTS: A stratified sample of 24 ambulatory, healthy, highly hypnotizable, volunteer college students selected for their above-average ability to alter skin temperature after hypnotic suggestions and their positive baseline responses to VZ antigen. There were 11 males and 13 females with a mean +/- SD age of 22 +/- 6 years. The mean +/- SD hypnotizability score (Harvard Group Scale of Hypnotic Susceptibility) was 11 +/- 1. INTERVENTIONS: Intradermal skin testing with VZ antigen (Mantoux method) and hypnotic suggestion. MAIN OUTCOME MEASURES: Areas of induration of the DTH response measured at 24 and 48 hours after injection of antigen. RESULTS: The area of the DTH response was not affected by the experimental interventions. The area of erythema was likewise unaffected. CONCLUSIONS: Our subjects were unable to alter their DTH responses using hypnotic suggestion.

New trends in combined use of gonadotropin-releasing hormone antagonists with gonadotropins or pulsatile gonadotropin-releasing hormone in ovulation induction and assisted reproductive technologies.

The use of gonadotropin-releasing hormone agonists as adjunctive therapy with gonadotropins for ovulation induction in in vitro fertilization and other assisted reproductive technologies has become common clinical practice. With the recent advent of potent gonadotropin-releasing hormone antagonists free from the marked histamine-release effects that stymied earlier compounds, an attractive alternative method may be available. We have established the feasibility of combining gonadotropin-releasing hormone antagonist-induced inhibition of endogenous gonadotropins with exogenous gonadotropin therapy for ovulation induction in a nonhuman primate model. Here, the principal benefits to be gained from using the gonadotropin-releasing hormone antagonist rather than the gonadotropin-releasing hormone agonist are the immediate inhibition of pituitary gonadotropin secretion without the "flare effect," which brings greater safety and convenience for patients and the medical team and saves time and money. We have also recently demonstrated the feasibility of combining gonadotropin-releasing hormone antagonist with pulsatile gonadotropin-releasing hormone therapy for the controlled restoration of gonadotropin secretion and gonadal steroidogenesis culminating in apparently normal (singleton) ovulatory cycles. This is feasible only with gonadotropin-releasing hormone antagonists because, unlike gonadotropin-releasing hormone agonists, they achieve control of the pituitary-ovarian axis without down regulation of the gonadotropin-releasing hormone receptor system. This capacity to override gonadotropin-releasing hormone antagonist-induced suppression of pituitary-ovarian function may allow new treatment modalities to be employed for women who suffer from chronic hyperandrogenemia with polycystic ovarian disease.

GnRH antagonists suppress prolactin release in non-human primates.

GnRH antagonists, such as Antide, are being evaluated for potential contraceptive applications. Although their contraceptive efficacy clearly results from their rapid inhibitory effects on gonadotropin release, there remains the possibility of other incidental effects. Under certain physiological conditions, the release of prolactin (Prl) appears to be temporally related to the secretion of luteinizing hormone (LH) and hence by inference to the secretion of GnRH. Here, we examined the effects of the GnRH antagonist Antide on the release of LH and Prl. Under agonadal conditions, a remarkable concordance was seen between LH and Prl pulses with up to 100% of pulses being coincident. Administration of Antide resulted in a rapid parallel decline in both LH and Prl with LH levels falling by 50% within 2 h and Prl levels falling by 30-40%. At this dose of Antide (1.0 mg/kg, sc), pulsatile release of LH and Prl continued albeit at a much reduced amplitude. The administration of a bolus of exogenous GnRH in the face of GnRHant-induced suppression resulted in prompt release of LH and Prl in all 3 monkeys. Since Antide inhibits the release of LH and Prl in a parallel fashion, and GnRH re-stimulates the release of both hormones in a parallel fashion, we conclude that the synchronous pulsatile release of LH and Prl observed in the agonadal monkey is due to a direct action of GnRH. What this action is for Prl release, and how it relates to the control of dopamine or other neuroendocrine mechanisms normally controlling the release of Prl remains unclear. It also remains to be seen whether this GnRH antagonist-induced suppression of Prl will have physiologic significance.

Antide bioavailability: single dose administration for suppression of testosterone and inhibin in male monkeys.

The pharmacokinetics and pharmacodynamics of a single sc injection of Antide on testosterone (T) and inhibin secretion in intact male cynomolgus monkeys were examined. Fifteen primates were randomized to three groups receiving: propylene glycol and water vehicle, 3 mg/kg Antide, and 10 mg/kg of Antide. Antide at the 10 mg/kg dose caused long-term suppression of T ranging from 24-56 days. At the 3 mg/kg dose, suppression of T was of shorter duration. Serum Antide levels were significantly greater in the 10 mg/kg group than the 3 mg/kg group (p less than 0.02), both initially and through 35 days post-treatment. The duration of testosterone inhibition and sustained Antide levels were significantly correlated (p less than 0.01). Inhibin concentrations followed the same general pattern as testosterone reaching a nadir on day 21 post-treatment before subsequent recovery. The prolonged suppressive effect of Antide on T without detectable side effects makes this compound an excellent candidate for clinical evaluation.

Inhibition of pituitary gonadotropin secretion by the gonadotropin-releasing hormone antagonist antide. I. In vitro studies on mechanism of action.

The GnRH antagonist antide is among the most promising "third generation" compounds available for clinical evaluation. In primates, antide manifests prolonged (several weeks) and reversible inhibition of pituitary gonadotropin secretion after a single high dose injection. In the present study, we have examined the effects of antide on pituitary gonadotropin secretion in vitro. Dispersed anterior pituitary cells from adult female rats were plated (48 h; 5 x 10(5) cells/well), washed, and exposed to increasing concentrations of antide for up to 48 h. Media were removed, and cells were washed twice and then incubated with GnRH (1 x 10(-8) M) plus antide for 4 h. Media and cell lysates were assayed for LH/FSH by RIA. Antide had no effect on basal LH/FSH secretion at any dose tested (10(-6)-10(-12) M). In contrast, GnRH-stimulated LH/FSH secretion was inhibited by this GnRH antagonist in a dose- and time-dependent manner. When incubated simultaneously, antide blocked GnRH-stimulated gonadotropin secretion, with a maximal effect at 10(-6) M (ED50, 10(-7) M). Preincubation of pituitary cells with antide for 6-48 h before GnRH exposure shifted the dose-response curve to the left; the maximally effective dose was 10(-8) M; the ED50 was 10(-10) M antide after 48-h preincubation. Intracellular LH/FSH levels increased concomitant with the decrease in secreted gonadotropins. Total LH/FSH levels (secreted plus cell content) remained unchanged. The inhibition of LH secretion by antide was specific for GnRH-stimulated gonadotropin secretion; antide had no effect on K(+)-stimulated LH secretion. Moreover, antide had little or no residual effect on LH secretion; full recovery of GnRH responsiveness in vitro occurred within 4 h after removal of antide. Lineweaver-Burke analysis of antide inhibition of GnRH-stimulated LH secretion indicated that antide is a direct competitor of GnRH at the level of the pituitary GnRH receptor. In summary, antide is a pure antagonist of GnRH stimulation of gonadotropin secretion; no agonistic actions of antide were manifest in vitro. Moreover, antide has no apparent noxious or toxic effect on pituitary cells in culture; the actions of antide are immediately reversible upon removal of antide from pituitary gonadotropes. We conclude that the long term inhibition of gonadotropin secretion by antide in vivo is not due to deleterious effects of this compound at the level of the pituitary gonadotrope.

Effect of preoperative chemotherapy on mastectomy for locally advanced breast cancer.

Mastectomy is frequently performed after intensive chemotherapy for locally advanced breast cancer. The effects of preoperative chemotherapy on the postoperative course and the timing of subsequent adjuvant therapy, however, have not been defined. We therefore reviewed the perioperative course of 54 patients undergoing mastectomy after combination (CAMFPT) chemotherapy for stage IIIA,B (IIIA - 25 pts; IIIB noninflammatory - 5 pts; IIIB inflammatory-24 patients) breast cancer. A median of 7 cycles (6 months) of chemotherapy was administered preoperatively. Mastectomy was performed a median of 20 days after last chemotherapy; white blood cell count (WBC) and platelet counts returned to normal limits preoperatively. Total mastectomy with or without axillary node dissection was performed in 53 patients, and a Halsted radical mastectomy in 1 patient. Negative margins on breast and/or axillary tissue were achieved in 47 patients (87.0%). Postoperative complications included skin flap necrosis in 8 patients (14.8%), seroma formation in 5 patients (9.3%), and wound infection in 1 patient (1.9%). Median operative blood loss (550 cc), hospital stay (8 days), and duration of wound catheter drainage (6 days) were comparable to published reports for modified radical mastectomy without preoperative chemotherapy. Systemic chemotherapy was resumed a median of 16 days after mastectomy, and radiotherapy started a median of 33 days after mastectomy. These findings indicate that intensive preoperative chemotherapy does not increase the hospital course or the postoperative complications of mastectomy for locally advanced breast cancer. In view of the current interest in treatment of stage I and II breast cancer with preoperative chemotherapy, this information may be useful in their management as well.