Endometriosis: translation of molecular insights to management.

Endometriosis is a debilitating gynecologic disorder causing pelvic pain and infertility and characterized by the implantation of endometrial tissue to extrauterine locations. Though aspects of the condition remain enigmatic, the molecular pathophysiology of endometriosis appears to be clarifying. Estrogen dependence of the disease is a sentinel endocrine feature and reduction of estrogen bioavailability is the therapeutic principle upon which traditional treatment and prevention approaches have been based. Endometriosis is a chronic inflammatory condition associated with lesional neoangiogenesis and attenuated progesterone action at the level of the endometrium. The elucidation of the molecular pathways mediating these observations has revealed new targets for directed medical and surgical treatment. This paper will review current approaches to the management of endometriosis in the context of the molecular pathophysiology.

Hypercalciuria in a new rat model of hyperprolactinemia.

Hypercalciuria has been reported in rats with mild hyperprolactinemia due to implantation of anterior pituitary glands under the kidney capsule and in rats bearing transplantable tumors that secrete large amounts of prolactin (PRL) and growth hormone (GH). We studied Buffalo rats implanted subcutaneously with the new MMQ pituitary tumor line that secretes only PRL. Urinary calcium excretion increased as the tumors grew. Three weeks after tumor implantation in female rats, the urinary calcium excretion was 1.102 +/- 0.092 mg/100 g body weight (BW).24 hours compared with controls, 0.296 +/- 0.079, P less than .0005. Male tumor-bearing rats also had increased urinary calcium excretion compared with male controls. In tumor-bearing rats the urinary calcium excretion factored for urinary sodium excretion, dietary calcium intake, or urinary creatinine excretion was elevated. Urinary calcium excretion was correlated with serum PRL levels and with estimated tumor volume. Serum calcium, immunoassayable parathyroid hormone, and urinary cyclic adenosine monophosphate (cAMP) excretion were normal in the tumor-bearing rats. There was some evidence of loss of bone calcium in rats bearing the MMQ tumor, and serum levels of calcitonin were decreased. These results are similar to those found in anterior pituitary-grafted hypercalciuric rats. It is unlikely that parathyroid hormone (PTH) abnormalities are responsible for the hypercalciuria in the MMQ-bearing rats. The pituitary gland may have an effect on the distal renal tubule to decrease calcium reabsorption.

Characterization of a new animal model of chronic hyperprolactinemia.

Animal models of chronic prolactin (PRL) excess have included rats bearing transplantable pituitary tumors that have produced other hypophyseal hormones in addition to PRL. We report characterization of a new model, the Buffalo rat implanted with the MMQ tumor, a line developed from the 7315a line. Rats implanted with the MMQ tumor have serum PRL levels that increase with time and correlate with the estimated volume of the subcutaneous tumor. When rats are killed 4 weeks after implantation, serum PRL levels are strikingly higher in tumor-bearing rats compared with controls (females, 2,723 +/- 266 v 192 +/- 46 ng/mL, P less than .0001; males, 1,637 +/- 213 v 99 +/- 11 ng/mL, P less than .0001). Serum PRL levels measured by the Nb2 lymphoma assay were higher than immunoassay measurements in both tumor-bearing and control Buffalo rats. Sephadex chromatography of serum from tumor-bearing rats showed that most of the PRL immunoreactivity co-eluted with 125I-rPRL. Neither serum growth hormone (GH) nor luteinizing hormone (LH) levels were different from controls in tumor-bearing rats. Female MMQ-bearing rats had lower estradiol levels. At death, the wet weights of adrenal glands, kidneys, and gonads were not affected by the presence of tumor. In contrast, tumor-bearing rats had increased spleen weight and histological evidence of white pulp hyperplasia. The Buffalo rat implanted with the PRL-only MMQ tumor is a promising new tool for the study of chronic hyperprolactinemia.

Hypogonadism does not mediate urinary calcium loss in pituitary-grafted rats.

Rats rendered chronically hyperprolactinemic by implantation of extra anterior pituitary glands (AP) under the kidney capsule have excess urinary calcium excretion. Although serum testosterone levels are normal in male AP-grafted rats, more subtle androgen deficiency might contribute to the increased calcium loss. Female AP-grafted rats lose the normal estrous cycle, which might also alter calcium homeostasis. The urinary calcium and calcium/sodium excretion ratio in gonadectomized AP-grafted rats of both sexes were compared with that of otherwise intact AP-grafted rats and muscle-grafted control rats. AP-grafted rats had increased urinary calcium excretion and calcium/sodium excretion ratio, regardless of gonadal status. Treatment of castrated male AP-grafted animals with testosterone or dihydrotestosterone did not have a significant effect on urinary calcium loss, nor did estrogen replacement of ovariectomized female AP-grafted rats. These studies indicate that the hypercalciuria of the AP-grafted rat is not mediated via an anti-gonadal effect of the prolactin-secreting pituitary graft.