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Objective: To examine the role of intraoperative rapid parathyroid hormone (PTH) monitoring in the surgical management of hyperparathyroidism., Design: Thirty-eight-month retrospective review., Setting: Tertiary care academic medical center., Patients: One hundred consecutive patients undergoing surgery for primary hyperparathyroidism., Intervention: All patients underwent preoperative technetium Tc 99m sestamibi scan localization and intraoperative blood PTH monitoring by means of a rapid (12-minute) immunochemiluminometric assay., Main Outcome Measures: The influence of intraoperative PTH levels on extent of surgical dissection and achievement of postoperative normocalcemia., Results: Intraoperative PTH levels dropped an average of 64%, 75%, and 83% at 5, 10, and 20 minutes, respectively, after excision of all hyperfunctioning parathyroid tissue. A PTH decrease of 46% or more at 10 minutes and 59% or more at 20 minutes after excision of hyperfunctioning tissue was predictive of postoperative normocalcemia. In 79 patients (79%), the sestamibi scan provided accurate preoperative localization; all but 1 of these patients were treated successfully, most often with a limited, gland-specific dissection. In 24 patients with inaccurate, negative, or misleading preoperative sestamibi scans, 23 (96%) were treated successfully with the use of the intraoperative PTH assay., Conclusions: The rapid intraoperative PTH assay accurately predicts postoperative success in patients with primary hyperparathyroidism. The rapid PTH assay allows for greater confidence in performing limited dissections in well-localized uniglandular disease. In cases of inaccurate preoperative localization, the rapid PTH assay directly affects surgical decision making and provides greater confidence in determining when surgical success has been achieved.

Objective: To assess the diagnostic accuracy of fine-needle aspiration (FNA) and frozen section (FS) in nodular thyroid disease., Setting: Tertiary care academic medical center., Study Design: Retrospective review of 139 consecutive patients undergoing surgery for nodular thyroid disease. FNA and FS sensitivity, specificity, and accuracy were calculated with respect to permanent section histology., Results: Among 63 patients with an FNA interpreted as either benign (n = 38) or malignant (n = 25), FNA was accurate (sensitivity 89%, specificity 97%, accuracy 94%). FS identified only one case of carcinoma missed by FNA. Among 76 patients with a "suspicious" FNA, FS was reasonably accurate (sensitivity 67%, specificity 100%, accuracy 89%), but was deferred in 50% of cases., Conclusion: Given high FNA accuracy, more selective use of FS is suggested., Significance: The study results will assist with intra-institutional patient counseling and intraoperative decision-making with respect to FNA and FS results in patients with nodular thyroid disease.

Purpose: The authors have often observed on Tl-201 and Tc-99m sestamibi (MIBI) scans in patients with thyroid cancer a small focus of increased uptake in the right midparasternal region (focus A) or sometimes in the lower mid chest at the level of the lower sternum (focus B) just inferomedial to focus A. The objective of this study was to assess the frequency of this finding on Tl-201 MIBI studies, to assess the incidence of true pathologic lesions corresponding to these foci, and to identify their nature., Materials and Methods: One hundred ten whole body Tl-201 studies using 4 mCi (148 MBq) and 84 MIBI studies using 20 mCi (740 MBq: first-pass, planar, and SPECT images) were reviewed. The appearance of either focus A or focus B on three orthogonal SPECT images was correlated with an atlas of cross-sectional anatomy and computed tomography. If focus A was seen on the immediate static image (obtained at the end of the first-pass acquisition without moving the patient), this image was coregistered with a selected image from the first-pass study showing the superior vena cava and also with another selected image showing the ascending aorta., Results: Focus A was seen in 40% of Tl-201 scans and in 49% of MIBI scans, whereas focus B was seen in 20% of Tl-201 scans and 39% of MIBI scans. On correlation of the SPECT images with a cross-sectional anatomy atlas, focus A and focus B invariably corresponded to the superior portion of the right auricle and basal superoanterior right ventricular wall, respectively. These myocardial regions are prominent and sometimes appear as discrete foci because they are considerably thicker than other parts of the right atrial and right ventricular muscle, respectively, and because they are seen partly end-on in the anterior projection., Conclusions: The superior portion of the right auricle and basal superoanterior right ventricular myocardium often appear as isolated foci on whole-body Tl-201 and MIBl scans. Neither focus should be interpreted as a metastatic lesion in patients with possible cancer or as an ectopic parathyroid adenoma in patients with hyperparathyroid disease.

Study Objective: The chronically critically ill (CCI) are a subgroup of critically ill patients who have survived an acute critical illness but remain profoundly debilitated and ventilator dependent. We have previously shown that CCI patients have a very high prevalence of bone hyperresorption. The objective of this present study was to determine the biochemical response of bone hyperresorption in CCI patients to treatment with either calcitriol alone or calcitriol and pamidronate., Design: Retrospective survey., Setting: Respiratory care step-down unit (RCU) at a tertiary-care teaching hospital., Patients: Fifty-five ventilator-dependent CCI patients transferred from ICUs within the same institution who had elevated urine N-telopeptide (NTx) levels at RCU admission, who were treated with either calcitriol alone (n = 44) or calcitriol and pamidronate (n = 11), and who had urine NTx levels remeasured following treatment., Intervention: None., Measurements and Results: Patients treated with calcitriol alone had a significant reduction in serum parathyroid hormone (PTH; 93+/-145 pg/mL vs 40+/-28 pg/mL; p = 0.02) but not in urinary NTx (187+/-146 nmol bone collagen equivalents [BCE]/mmol creatinine [Cr] vs. 178+/-123 nmol BCE/mmol Cr, p = 0.59). In contrast, patients treated with both calcitriol and pamidronate had a significant decrease in urine NTx at follow-up (329+/-238 to 100+/-85 nmol BCE/mmol Cr; p<0.01) but not in serum PTH (36+/-29 to 53+/-51 pg/mL; p = 0.44)., Conclusion: The bone hyperresorption of CCI patients is PTH independent and biochemically responds to treatment with calcitriol and pamidronate but not calcitriol alone.

Objective: To determine the prevalence of hypotestosteronemia in chronically critically ill (CCI) men., Design: Prevalence survey., Setting: Step-down respiratory care unit (RCU) at a tertiary care teaching hospital., Patients: Thirty ventilator-dependent CCI men transferred from intensive care units (ICUs) within the same institution., Interventions: None., Measurements and Main Results: Total testosterone and bioavailable testosterone (bioT) concentrations were measured within 48 hrs of RCU admission. Patients were hospitalized a median of 40 days (range, 9-185 days) before RCU admission, with a median ICU length of stay of 25 days (range, 9-177 days). At RCU admission, total testosterone concentrations averaged 104+/-96 ng/dL, with average bioT concentrations of 19+/-20 ng/dL (16+/-9% of total testosterone). Twenty-nine of the 30 patients (96%) had bioT concentrations well below the lower limit of normal for their age range. bioT concentrations, expressed as a percentage of the normal mean for each patient's age range, were positively correlated with the number of days that the patient was in the ICU before transfer to the RCU (n = 30, r2 = .17, p = .025). However, if the single patient who remained in the ICU for 177 days was excluded, this correlation disappeared (n = 29, r2 = .07, p = .09). No other relationship was found between bioT concentrations and any other variable, including type of patient, ICU length of stay, reason for either initial admission to the ICU or prolonged mechanical ventilation, type of nutritional support, or use of dopamine., Conclusions: CCI men have a very high prevalence of hypotestosteronemia, which may impede their recuperation and rehabilitation. Further studies are needed to determine whether additional pharmacologic treatment with testosterone can improve the recovery of these patients.

Study Objective: Chronically critically ill (CCI) patients are primarily elderly people who have survived a life-threatening episode of sepsis but remain profoundly debilitated and ventilator dependent. The objective of this study was to determine the prevalence of bone hyperresorption and parathyroid hormone (PTH)-vitamin D axis abnormalities in these patients., Design: Prevalence survey., Setting: Respiratory care step-down unit (RCU) at a tertiary care teaching hospital., Patients: Forty-nine ventilator-dependent CCI patients transferred from ICUs within the same institution., Intervention: None., Measurements and Results: N-telopeptide (NTx) levels in 24-h urine collections and serum intact PTH, 25-vitamin D, and 1,25-vitamin D levels were measured within 48 h of RCU admission. Patients were hospitalized a median of 30 days before RCU admission. Four patients (9%) had normal NTx and PTH levels. Forty-five patients (92%) had elevated urine NTx levels consistent with bone hyperresorption. Nineteen patients (42% of total patients) had elevated PTH levels consistent with predominant vitamin D deficiency, 4 patients (9%) had suppressed PTH levels consistent with predominant hyperresorption from immobilization, and 22 patients (49%) had normal PTH levels consistent with an overlap of both vitamin D deficiency and immobilization. There were no differences in vitamin D metabolites among these groups., Conclusions: CCI patients have a high prevalence of bone hyperresorption in which PTH levels may clarify the cause. Further studies will determine the efficacy and cost-effectiveness of routine NTx and PTH screening in these patients and the role of vitamin D and antiresorptive therapies.

The purpose of this study is to investigate the association of hypothalamic-pituitary axis abnormalities with the free thyroxine index (FTI) in critically ill patients. Fourteen critically ill patients and twenty healthy volunteers were studied using combined anterior pituitary gland testing with CRF, GHRH, TRH, and GnRH. The subjects were grouped as follows: I-healthy volunteers; II-sick/normal FTI; and III-sick/low FTI. Serial measurements of hormones were performed over a two-hour interval and the following parameters were measured: baseline level, response amplitude and time to maximal response. Response velocities and area-under-the-curves (integrated responses) were also computed. Group III had a longer mean ICU duration prior to testing than group II. Urinary cortisol, serum cortisol and serum PRL levels were elevated in groups II and III. However, group III had lower baseline ACTH levels, slower ACTH and TSH response velocities and decreased PRL integrated responses. Cortisol response parameters were similar between groups II and III. There were no differences in LH, FSH or GH response velocities or integrated responses among the 3 groups. These data confirm that critically ill patients develop hyperprolactinemia and hypothalamic-pituitary-adrenal axis activation but when a low FTI exists, a plurality of changes occur reflected by attenuated PRL, TSH and ACTH responses despite unaffected adrenal cortisol output.

Objective: To demonstrate that after spinal cord injury (SCI) suppression of the parathyroid-vitamin D axis is associated with the degree of neurologic impairment and not the level of injury., Design: A retrospective analysis of clinical and biochemical data obtained from hospital records of patients with SCI compared to a control group of patients with traumatic brain injury (TBI)., Setting: The inpatient rehabilitation unit of a tertiary care hospital., Subjects: The medical records of 82 consecutive admissions to the rehabilitation unit with a diagnosis of SCI or TBI were reviewed. Patients with SCI were classified by the American Spinal Injury Association (ASIA) impairment scale and then grouped based on the completeness and level of injury., Main Outcome Measure: Comparisons of serum parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D (1,25-D) were planned. Multiple comparisons were performed for total and ionized serum calcium levels, serum phosphorus levels, and 24-hour urinary calcium excretion rates to reflect changes in mineral homeostasis. Multiple comparisons were also performed for serum albumin, prolactin, thyroid function tests, and AM cortisol levels, as well as 24-hour urinary urea nitrogen and cortisol excretion rates to reflect metabolic responses to stress., Results: Patients with SCI had significant suppression in PTH (p < .000009) and 1,25-D (p < .02) levels with elevated phosphorus (p < 0.03) and prolactin (p < .03) levels compared to patients with TBI. Also, more patients with SCI were hypoalbuminemic (p < .003) than patients with TBI. Patients with complete SCI (ASIA A) had more suppressed PTH (p < .03) and higher urinary urea nitrogen (p < .05) levels than SCI patients with incomplete injuries (ASIA B-D). Patients with complete, but not incomplete, SCI had lower albumin levels than patients with TBI (p < .05). These differences were not found between patients with tetraplegic and paraplegic SCI. ASIA motor scores did not correlate with any of the measured parameters but when used as a covariate did abolish differences in PTH and 1,25-D among the study groups by ANOVA., Conclusion: In patients with SCI, the degree of neurologic impairment, and not the level of injury, is associated with PTH suppression and markers of metabolic stress.

We present the unusual case of a 29-year-old man diagnosed in 1975 with papillary carcinoma of the thyroid metastatic to regional lymph nodes. The patient underwent surgical resection, postoperative iodine-131 (131I) radioablation and levothyroxine suppression. He was subsequently lost to follow-up. In 1991, he presented with extensive metastatic disease that was not demonstrable on whole-body 131I imaging, but was seen on computerized tomography and whole-body thallium chloride scanning. The patient was treated with cisplatin (Platinol) and doxorubicin (Adriamycin). Repeat 131I imaging after three cycles of chemotherapy showed significant 131I uptake in previously non-iodine-concentrating lesions. The patient was subsequently treated with 200 mCi 131I. We postulate this patient's non-iodine-concentrating thyroid cancer may have become functional by either a differentiating effect of chemotherapy on the tumor cells, or perhaps a selective cytotoxicity against nonfunctional, less differentiated papillary thyroid cancer cells, or both. This would allow more functional differentiated cells to overgrow and become the predominant cell type in the lesions. Chemotherapy may be beneficial in patients with advanced non-iodine-concentrating differentiated thyroid carcinoma by inducing radioiodine uptake and allowing subsequent radioiodine therapy. The possible mechanisms of induction of iodine uptake by chemotherapy are discussed.

We used a porcine endotoxemic model of acute lung injury to compare extravascular lung water (EVLW) measured by right transthoracic bioimpedance to postmortem gravimetric EVLW measurements. Adult pigs were randomized into control (N = 5) or endotoxin groups [150 microgram/kg Escherichia coli lipopolysaccharide B for 1 hr followed by 3 hr of resuscitation for a thermodilution cardiac output less than 90% of baseline using either isotonic saline (N = 5) or isooncotic albumin (N = 5)]. Right lung resistance was measured using a novel electrode array and a highly sensitive analyzer and was used to calculate right lung resistivity. At the end of the experiment, animals in the endotoxin-albumin group had higher gravimetric EVLWs than those in the endotoxin-saline or control groups (P < 0.05). Right lung resistivity corrected for body weight significantly correlated with gravimetric EVLW (r2 = 0.49; SEE = 0.96; P = 0.0038). Using multiple regression analysis, a predictive equation for EVLW based on right lung resistivity, body weight, and mean pulmonary artery pressure was generated (r2 = 0.81; SEE = 0.60; P < 0.0001). These results demonstrate that right lung resistivity measurements can provide a noninvasive estimate of EVLW. In addition, crystalloid may be preferable to colloid for fluid resuscitation in noncardiogenic pulmonary edema.

Unlabelled: The purpose of this study was to determine the concordance and discordance between diagnostic 131I and 201TI whole-body scintigraphy in patients with differentiated carcinoma of the thyroid., Methods: Following thyroidectomy for differentiated thyroid carcinoma, 50 patients underwent whole-body 131I and 201TI scanning (60 pairs of scans in total). Fifteen pairs of studies were obtained before ablative therapy, 30 pairs after ablative therapy and 15 pairs after 131I therapy for metastatic disease. Serum thyroglobulin levels were concurrently determined by radioimmunoassay., Results: Thirty-six 131I whole-body scans (in 34 patients) showed residual uptake in the neck, but only six (17%) of the corresponding whole-body thallium studies had detectable uptake in the neck. Fourteen 131I scans (in nine patients) identified multiple metastatic lesions, whereas the thallium scans were interpreted as either negative, nonspecific or showing fewer lesions. In four study pairs, the thallium scans showed solitary lesions that were not detected by the corresponding radioiodine scans. In 16 scans, the thallium studies gave false-positive results., Conclusion: Iodine-131 scintigraphy for differentiated thyroid carcinoma is more sensitive and more specific than 201TI scintigraphy for detection of distant metastases and residual activity in the neck following thyroidectomy.

A 67-yr-old woman who underwent total thyroidectomy 32 yr ago developed accelerated hyperthyroidism after injection of iodinated contrast media to evaluate a left hemipelvis mass. The patient was managed with propylthiouracil, beta-blockers and digoxin. Whole-body 201TI and 131I scans demonstrated a functioning metastasis in the left hemipelvis where biopsy revealed a well differentiated follicular thyroid carcinoma. Palliative external beam radiotherapy was administered. The patient then received radioiodine treatment with granulocyte colony-stimulating factor to minimize bone marrow toxicity. Clinically significant thyrotoxicosis occurring in metastatic thyroid carcinoma is rare and results from abnormal ectopic thyroidal tissue iodine metabolism. Iodide-containing medications and contrast media should be avoided in patients with functioning thyroid metastases to prevent abrupt increases in circulating thyroid hormone levels.

Endocrinologists are uniquely suited to provide consultation in the new field of metabolic support. This specialty incorporates management of electrolyte and mineral disorders, diabetes mellitus, and malnutrition. Principles of formulation of parenteral nutrition are discussed, with an emphasis on distinguishing marasmus from kwashiorkor types of cachexia, disease-specific treatment, nutritional pharmacology, and relevant controversies.

In the present study, we combined a powerful and novel receptor binding data analysis technique. Fourier-derived affinity spectrum analysis (FASA), with the nonlinear regression analysis program LIGAND to resolve benzodiazepine receptor heterogeneity in rat spinal cord. With FASA, we identified three distinct [3H]Ro15-1788 binding populations: two high-affinity sites (0.4 and 5 nM) for the radioligand and a lower-affinity site (150 nM) that is insensitive to the imidazopyridine alpidem. With the affinities for the radioligand determined with FASA, the Ki values of 13 competing ligands were calculated with LIGAND. All of the ligands studied displayed the highest affinity for site 1 (the highest-affinity [3H]Ro15-1788 binding site), with the exception of AHR 11797. Site 2 had high affinity for Ro15-1788, lower affinity for flunitrazepam and beta-CCM and very low, but measurable, affinity for zolpidem. The alpidem-insensitive binding site, studied in isolation by performing competitive binding assays in the presence of 65 microM alpidem, showed relatively low affinity for all of the ligands studied, and its physiological relevance is not yet known.

Thallium imaging is increasingly being used to evaluate the thyroid. Uptake patterns of 201Tl in benign and malignant thyroid nodules have been described. Thallium localizes all thyroid tissue with possibly different rates of washout in benign and malignant nodules. This case demonstrates a follicular adenoma presenting 123I as a clinically palpable nodule with nonvisualization of the remainder of the thyroid gland consistent with the diagnosis of an autonomously hyperfunctioning module. Subsequent thallium scanning revealed a complete reversal of tracer distribution with lack of uptake of 201Tl in the nodule while the rest of the gland showed normal thallium accumulation. Surgical excision of the nodule demonstrated follicular adenoma.

Existence of proopiomelanocortin (POMC) messenger RNA (mRNA) and related peptides in extrapituitary sites has been demonstrated in immune cells, although the particular type of immune cell has been the source of considerable debate. Specifically, double labeling studies have shown that POMC peptide expressing cells in the spleen represent a subpopulation of red pulp macrophages, while splenic lymphocyte areas are POMC negative. In addition, it has also been reported that peripheral blood leukocytes express the POMC gene. Using a sensitive solution hybridization technique with a POMC exon-1 RNA probe, we detected 70 +/- 20 fg and 65 +/- 5 fg POMC mRNA per microgram total RNA in whole spleen and lung, respectively, approximately 20,000-fold lower concentrations than found in the neurointermediate lobe of the pituitary. The presence of nuclease protected full length exon-1 bands, rather than the 5' truncated POMC RNAs seen in many nonpituitary tissues, indicates transcription initiation at the normal pituitary POMC promoter site in lung and spleen. In order to localize POMC gene expression in these tissues we employed an in situ hybridization method. There was an intense signal in a small population of large mononuclear cells scattered throughout the splenic red pulp and lung parenchyma. In the lung, these cells were concentrated in the periarteriolar zone in a manner suggestive of migration from the intravascular lumen. These cells had a histomorphology suggestive of monocyte-macrophages. POMC mRNA was undetectable in the splenic white pulp and bronchus-associated lymphoid tissue, indicating an absence of POMC gene expression in splenic and lung lymphocytes. Immunocytochemical studies suggested that POMC-positive cells made up a subpopulation of cells expressing the rat monocyte-macrophage markers ED1 and ED2. Similarly, the distribution of Jenner-Giemsa stained monocyte-macrophages appeared to overlap with POMC positive cells. Studies with anti-rat beta-endorphin antisera revealed scattered cells in the splenic red pulp and lung parenchyma, suggesting that the POMC mRNA is translated in these cells. In summary, POMC mRNA is expressed in a small population of monocyte-macrophage-like cells in lung and spleen but not in lymphocytes in these tissues.

The computer program described in this paper facilitates resolution of binding affinity heterogeneity by transforming binding curve data (bound versus free) into affinity spectra (density versus affinity). The original program, written in FORTRAN, is extended and presented here in the language C. New applications include an ability to transform competition curves into affinity spectra and to evaluate the effects of sampling and experimental error on spectrum analysis. We propose that this program be incorporated in the routine evaluation of binding systems.

The clinical presentation and management of the hirsute woman is illustrated in cases of idiopathic hirsutism, polycystic ovarian disease, and nonclassical congenital adrenal hyperplasia. Therapeutic regimens manage hyperandrogenic signs, induce ovulation, and protect the endometrium.

Dopamine (DA), norepinephrine (NE), epinephrine (E), 3,4-dihydroxyphenylglycol (DOPEG) and dihydroxyphenylacetic acid (DOPAC) were determined simultaneously by a radioenzymatic, thin-layer chromatographic assay able to detect 1-10 pg of the parent compounds and 80-120 pg of their metabolites. A localization study of these compounds in 20 micro-dissected hypothalamic and limbic structures and the anterior and posterior pituitary glands of male rats was completed. DOPAC was detectable in 14 of 22 structures with the lowest DOPAC/DA ratio being found in the caudate nucleus (7.1%) and the highest in the medial aspect of the ventromedial nucleus of the hypothalamus (422.0%). There was a higher DOPAC/DA ratio in the lateral (21.5%) than in the medial (11.3%) portion of the median eminence suggesting that a greater portion of released DA in the medial median eminence enters the portal circulation. DOPEG was detectable in 6 of 22 structures with DOPEG/NE ratios ranging from 8% (interstitial nucleus of the stria terminalis, ventral aspect) to 32% (medial median eminence). A poor correlation exists between DOPAC and DA concentrations in the various brain regions while there was a stronger relationship between DOPEG and NE concentrations. Male rats were rendered hyper-prolactinemic for 48 hours with injections of ovine prolactin (oPRL) every 8 hours (4 mg/kg body weight sc). In such rats there was a suppression of endogenous rat PRL (rPRL) secretion, the DOPAC/DA ratio increased 2.2-fold in the medial (MEm) and 1.9-fold in the lateral median eminence (MEl), and the DA concentration in the anterior pituitary also increased 2.6-fold. In 10 day postpartum lactating rats, suckling produced marked increases in serum rPRL but no change in DOPAC/DA ratios in the ME or in the DA concentration in the anterior pituitary. The data reveal a wide range of DOPAC/DA ratios (7-422%) in brain regions containing cell bodies, axons and terminals of the different dopaminergic neuronal tracts in brain and pituitary. Considering the DOPAC/DA ratios in the MEm and MEl, it is suggested that a large perturbation of dopaminergic transmission produces a significant ratio change while a smaller perturbation is not detected by this index of neuronal metabolism.

A study of 19 nonhirsute women with weight loss-related hypothalamic oligo-amenorrhea revealed evidence of multifollicular ovaries in 17. Enlarged ovaries greater than 10 cm3 were found in 8 of these subjects (42.1%). High-resolution real-time ultrasonography of the pelvis of 19 weight loss-related oligo-amenorrheic subjects revealed a mean +/- SD maximum ovarian volume (MOV) of 11.8 +/- 7.0 cm3, which was significantly different from those of control subjects whose mean +/- SD MOV was 5.2 +/- 1.9 cm3 (P = less than 0.001). The data do not allow a specific ultrasonographic distinction between hyperandrogenic women with polycystic ovarian disease and women with weight loss-related hypothalamic amenorrhea.

A 28-year-old man presented with azoospermia, low plasma testosterone levels, and an elevated follicle stimulating hormone (FSH) concentration. Bilateral testicular biopsies revealed tubular atrophy with normal-appearing Leydig cells. One year later, symptoms and signs consistent with myotonic dystrophy (MyD) were noted. The rarity of male hypogonadism preceding the neurological manifestations of MyD is stressed.

We hypothesize that the Stein-Leventhal syndrome (type 1 polycystic ovarian disease: SLS-PCOD-I) results from an aberrant puberty. Abnormal neural development in the brain decreases the hypophyseal set-point for negative and positive ovarian hormone feedback. This generates a condition whereby hypophyseal luteinizing hormone (LH) secretion is inappropriately elevated compared to hypophyseal follicle-stimulating hormone (FSH) secretion and is thus termed inappropriate gonadotropin secretion (IGS). The events which create an initial state of IGS are referred to as the "generator" stage. IGS is maintained by ovarian-derived hyperandrogenemia and increased peripheral aromatization of androgens yielding elevated free serum estrone (E1) and unbound estradiol (E2) levels. E1 suppresses release of hypophyseal FSH while E2 exerts positive feedback on LH pulsatile release by increasing pituitary sensitivity to gonadotropin-releasing hormone (GnRH). Diminished circulating FSH levels decrease granulosa cell aromatase activity sufficiently to cause suboptimal ovarian conversion of LH-induced thecal androgens into estrogens. Consequently, chronic local ovarian hyperandrogenemia with associated arrested follicle maturation results in chronic anovulation. Furthermore, an elevated circulating LH/FSH ratio stimulates early development and proliferation of immature follicles causing the appearance of polyfollicular ovaries. In this effector stage of PCOD-I, a vicious cycle is fashioned wherein IGS causes polyfollicular ovaries and increased ovarian androgen production which, in turn, promotes IGS. We suggest that the etiology of this disease involves an aberrant puberty that establishes a persistent faulty hypothalamic-hypophyseal-ovarian axis.

Previous studies from our laboratories demonstrated that cells from a human endometrial adenocarcinoma cell line (Ishikawa) responded to estradiol whereas cells from another endometrial cancer line (HEC-50) did not. In an attempt to identify factors responsible for the observed estrogen insensitivity we compared the characteristics of the estradiol receptor (ER) systems in Ishikawa and HEC-50 cells. Saturation analyses of cytosolic estrogen binders were performed over a 0.1-70 nM range of [3H]estradiol concentrations. Equilibrium dissociation constants and number of binding sites were determined by graphic analysis of Scatchard plots or computed by applying Fourier-derived affinity spectrum analysis (FASA) of the binding data. No significant differences were noted in the dissociation constants (Kd approx. 0.6 nM) or number of binding sites (approx. 6-10 fmol/mg protein) for the single binder that could be evaluated by the graphic method in cytosol from the two cell lines. However, 2 binders in Ishikawa cells (Kd approx. 0.2 and 6 nM) could be detected by the FASA method; the higher affinity binder in HEC-50 cells could not be clearly demonstrated. Structural differences in the specific estrogen binders which might distinguish HEC-50 from Ishikawa cells or normal endometrial tissue were investigated by using the anti-ER monoclonal antibody JS 34/32. Interaction of the antibody with [3H]estradiol binders of estrogen-responsive cells and tissue was evident from the formation of labeled complexes that were shown to sediment faster in glycerol density gradients and could be immunoprecipitated with Protein A attached to Sepharose beads. In contrast, the antibody did not recognize labeled specific binders in the HEC-50 cells. Furthermore, [3H]estradiol receptors in Ishikawa cells could be transformed into a species that exhibited increased hydrophilicity, evident from its binding to DNA-cellulose, whereas binders from HEC-50 could not. These results indicate that the lack of responsiveness of HEC-50 cells to estrogens might be due to structural or functional alterations in the ER protein resulting in a loss of its capability to undergo estrogen-directed conformational changes required for biological activity.

A new mathematical method of analyzing radioreceptor assay data is presented. When there are many binding classes with different affinities, the probability-density function B(p) is described by the equation B(p) = (integral negative infinity to infinity) q(k)f(p-k)dk, where q(k) is the affinity spectrum (density of a particular binding class as a function of affinity) and f(p-k) is a probability function (probability that dissociation constants will fall between k and p-k, where p is the free ligand concentration). This equation is solved for q(k) and evaluated explicitly by Fourier transformation, namely, q(w) = b(w)/f(w), where w is frequency. Since division by f(w) can amplify and high frequency noise present in the experimental data, a Gaussian smoothing function is introduced thus: qs(w) = q(w)e(-w/W0)2, where W0 is a constant. This produces an affinity spectrum defined as a plot of the number of binding sites, qs(k), versus their respective dissociation constants, k. Using a FORTRAN computer program, we verify this algorithm using simulated data. We also apply the procedure to resolve heterogeneous populations of estrogen binders in human endometrium using [3H]estradiol as ligand. Two estrogen binder classes are revealed with dissociation constants approximately 2.5 natural logarithmic units apart. We identify one high-affinity (Kd = 0.18 nM)-low density (70 pM [or 72 fmol/mg protein]) subpopulation and one low affinity (Kd = 2.5 nM)-high density (101 pM [or 102 fmol/mg protein]) subpopulation of estradiol binders. The management of experimental error, sampling limitations, and nonspecific binding are discussed. This method directly transforms experimental data into an easily interpretable representation without mathematical modeling or statistical procedures.

We have designed a cyclic regimen for the treatment of osteoporosis based on the activate, depress, free, and repeat (ADFR) concept. Osteoclastic bone resorption is activated by 7 days of oral neutral phosphate and inhibited with a brief pulse (5 days) of etidronate disodium at a high dose (20 mg/kg body weight). Patients next take calcium supplements for 48 days before resuming phosphate to enter the next cycle. Osteoporotic women increased the bone mineral density of the lumbar spine at 6 months by 7.2 +/- 5.2% (mean +/- SD, N = 14) and at 12 months by 8.2 +/- 4.0% (N = 8). Control observations in regularly exercising postmenopausal women (N = 30) showed no significant change in spine mineral density after 20 months (0.5 +/- 3.2%), confirming the stability of the measurement technique. The two patients who responded poorly to the cyclic regimen each showed a blunted rise in serum PTH during oral phosphate administration, suggesting that the rise in PTH induced by oral phosphate may be an important component of this cyclic regimen. This preliminary study does not identify which component or components of the regimen are responsible for the increase in bone mass but provides positive encouragement for randomized studies designed to determine the optimum dosage, duration, and timing of each component of the regimen.

A patient with pseudoxanthoma elasticum was documented to be hyperphosphatemic and mildly hypercalcemic for six years. Complications included metastatic calcification, absorptive hypercalciuria, and renal insufficiency. The 1,25-dihydroxyvitamin D value was elevated, despite normal serum parathyroid hormone values, high serum phosphate levels, and renal insufficiency. Either increased dietary calcium or prednisone seemed to suppress the 1,25-dihydroxyvitamin D value. Nephrolithiasis or abnormalities suggestive of pseudoxanthoma elasticum occurred in the patient's father, daughter, and several siblings, suggesting a distinct familial syndrome in which connective tissue changes are accompanied by abnormalities of phosphorus and vitamin D metabolism that may resemble those in the syndrome of familial tumoral calcinosis. Nine similar cases were described before 1970.

The authors describe 15 cases with evidence of hypothalamic dysfunction 2 to 9 years following megavoltage whole-brain x-irradiation for primary glial neoplasm. The patients received 4000 to 5000 rads in 180- to 200-rad fractions. Dysfunction occurred in the absence of computerized tomography-delineated radiation necrosis or hypothalamic invasion by tumor, and antedated the onset of dementia. Fourteen patients displayed symptoms reflecting disturbances of personality, libido, thirst, appetite, or sleep. Hyperprolactinemia (with prolactin levels up to 70 ng/ml) was present in all of the nine patients so tested. Of seven patients tested with thyrotropin-releasing hormone, one demonstrated an abnormal pituitary gland response consistent with a hypothalamic disorder. Seven patients developed cognitive abnormalities. Computerized tomography scans performed a median of 4 years after tumor diagnosis revealed no hypothalamic tumor or diminished density of the hypothalamus. Cortical atrophy was present in 50% of cases and third ventricular dilatation in 58%. Hypothalamic dysfunction, heralded by endocrine, behavioral, and cognitive impairment, represents a common, subtle form of radiation damage.