Cytoplasmic and nuclear estrogen and progesterone receptors in male breast cancer.

Cytoplasmic estrogen receptors were detected in 12 of 13 male breast cancer tumors. There was no significant correlation of receptor levels with the age of the patient, size and histological grading of the tumor, and stage and nodal involvement of the disease. Nuclear estrogen receptors were found in eight of 10 tumors and six of nine patients had tumors positive for cytoplasmic progesterone receptors, two of which were also found to contain nuclear progesterone receptors. The presence of cytoplasmic progesterone receptors, in addition to cytoplasmic and nuclear estrogen receptors, may be indicative of truly hormone-dependent tumors in male breast cancer. Treatment offered to patients included surgery, X-ray therapy, chemotherapy, and orchiectomy, but as yet, no general conclusions of the efficacy of the therapeutic regime can be drawn.

Estrogen and progesterone receptors in breast cancer among women of different racial groups.

No differences in steroid hormone receptor status were detected in premenopausal breast cancer patients of different races. In postmenopausal women, 65% of Whites were found to have tumors positive for cytoplasmic estrogen receptors (CER) compared with 58, 52, and 41% in women of mixed race, Blacks, and Asians, respectively. The proportions of tumors which contained a full complement of receptors (CER, nuclear estrogen receptors, and cytoplasmic progesterone receptors) were similar in Blacks, Whites, and Asians in each menopausal group. In postmenopausal patients, significantly fewer White women had tumors devoid of all receptors, while having a higher incidence of tumors with an abnormal or defective receptor distribution. Neither the stage of the disease nor the degree of nodal involvement appeared to affect receptor status in any population group, but very large tumors had fewer receptors. White patients with large neoplasms had a significantly higher incidence of CER than Blacks or Asians. Similar observations were made for White patients presenting with Stage III disease, whose tumors were greater of histological Grade I tumors were positive for CER, compared with Grade III neoplasms. Indications are that receptor status is inherent to the natural history of the disease and is not influenced by clinical features.

Obesity does not modulate insulin secretion in Indian patients with non-insulin-dependent diabetes in the young.

The insulin response to a 100-g oral glucose load was studied in 40 obese (percent desirable weight greater than or equal to 120%) and 40 nonobese (less than 120%) age- and sex-matched Indian patients with non-insulin-dependent diabetes in the young. There were no significant differences between the obese and nonobese patients with respect to their insulin and glucose responses. Thus, it appears that obesity does not exert a significant modulating effect on insulin secretion in patients with fasting hyperglycemia.

Nephropathy in Indian patients with non-insulin-dependent diabetes in the young.

In 85 patients diagnosed as having non-insulin-dependent diabetes in the young (NIDDY), 6 were found to have nephropathy. The duration of diabetes ranged from 2 to 17 yr; 5 of the 6 patients had retinopathy as evidenced by fluoroscein angiography (3 with proliferative changes). All 6 patients had a 24-h urinary protein excretion greater than 0.5 g and a glomerular filtration rate less than 80 ml/min. Serum beta 2-microglobulin levels were increased in all 6 patients, while only 3 had increased serum creatinine levels.

Acute insulin response to glucagon, tolbutamide, and glucose in non-insulin-dependent diabetes of the young.

Acute insulin release in response to maximal intravenous doses of glucose (0.5 g/kg), tolbutamide (1 g), and glucagon (1 mg) was studied in 10 subjects with non-insulin-dependent diabetes of the young (NIDDY) and 10 age-, sex-, and weight-matched controls. Diabetic subjects had attenuated insulinemic responses to all three stimuli, in comparison with control subjects. However, insulin responses to glucagon and tolbutamide were higher than those obtained with intravenous glucose. This study demonstrates that the pancreatic beta-cell is more responsive to nonglucose secretagogues than to glucose stimuli in individuals with NIDDY.

Evidence for insulin resistance in nonobese patients with polycystic ovarian disease.

In this study seven normal weight Indian patients with polycystic ovarian disease (PCOD) with no evidence of acanthosis nigricans and 7 age- and weight-matched normal Indian women were studied to determine whether PCOD patients were insulin-resistant. While all 14 women had normal glucose tolerance, the PCOD women had significantly higher mean plasma glucose levels at 30 and 60 min and higher mean incremental glucose areas [incremental areas: PCOD, 9.0 +/- 2.2 (+/- SEM); normal women, 4.0 +/- 0.8 mmol/L; P less than 0.05]. Insulin responses were significantly higher in the PCOD compared to normal women (incremental areas: PCOD, 623.8 +/- 78.3; normal women, 226.2 +/- 30.3 microU/mL; P less than 0.001). Both serum testosterone and androstenedione levels correlated with the insulin areas (r = 0.82; P less than 0.001 and r = 0.86; P less than 0.001, respectively). [125I] Insulin binding to erythrocytes revealed decreased maximum specific binding in the PCOD women (6.9 +/- 0.6%) compared to that in normal women (9.2 +/- 0.7%; P less than 0.02). While Scatchard analysis revealed similar receptor numbers, ID50 values demonstrated decreased receptor affinity in the women with PCOD. In conclusion, in the absence of acanthosis nigricans, nonobese patients with PCOD are insulin resistant, and this insulin resistance correlates with the hyperandrogenism.

Amniotic membrane production of prostaglandin F2 alpha is reduced in dysfunctional human labor: results of in vivo and in vitro studies.

Mobilization of arachidonic acid from glycerophospholipids and prostaglandin (PG) release from fetal membranes were studied in women with dysfunctional labor in the absence of cephalopelvic disproportion or fetal malposition. Using superfusion of intact amnion and chorion, we found a slight decrease in PGE and a more significant decrease in PGF release by the amniotic side of the fetal membrane obtained from women with dysfunctional labor compared to that in women with normal labor (PGE: normal labor, 2992 pg/cm2.h; dysfunctional labor, 1846 pg/cm2.h; P less than 0.05; PGF: normal labor, 662 pg/cm2.h; dysfunctional labor, 204 pg/cm2.h; P less than 0.02). Release of both prostanoids was significantly greater from the amniotic side in tissues obtained after labor compared to that in prelabor tissue. Analysis of arachidonic acid (by gas liquid chromatography) and phospholipid content (by two-dimensional thin layer chromatography) confirmed metabolic disposal of arachidonic acid from the amnion after the onset of labor. However, no difference in either phospholipid or phospholipase A2-releasable arachidonic acid of individual phospholipid classes was found in amnion tissue from women with normal and dysfunctional labor, suggesting similar activities of phospholipase A2 in these two groups. The finding of decreased free and phospholipase A2-releasable arachidonic acid of the total lipid extract of the amnion of women with dysfunctional labor could suggest further metabolic exhaustion of the substrate or failure of liberation of this fatty acid from glycerophospholipids by enzymes other than phospholipase A2, such as phospholipase C or diacyl and monoacylglycerolipases.

Impaired corpus luteum function in ectopic pregnancy cannot be explained by altered human chorionic gonadotropin.

We studied the cause of the low serum progesterone, 17 beta-estradiol, and 17-hydroxyprogesterone levels that occur in women with an ectopic pregnancy. Only women who had been amenorrheic for less than 8 weeks were studied in order to assess corpus luteum rather than placental biosynthesis of these steroids; each woman with an ectopic pregnancy was matched to a woman with a normal intrauterine pregnancy on the basis of serum intact hCG levels within 10% of one another to obviate the influence of different levels of this luteotropic hormone. Every woman with an ectopic pregnancy had lower serum progesterone, estradiol, and 17-hydroxyprogesterone levels than her matched normal pregnant pairmate (median values: progesterone, 27.9 vs. 83.5 mmol/L; estradiol, 0.36 vs. 1.79 nmol/L; 17-hydroxyprogesterone, 4.95 vs. 22.1 nmol/L, respectively; all P less than 0.002). The ratios of intact hCG, measured by immunoradiometric assay, to hCG, measured by a hCG beta-specific RIA, were similar in the two groups. Serum hCG bioactivity was assayed by measuring the ability of serum to stimulate testosterone secretion from mouse Leydig cells. The mean biological to intact immunological hCG ratios were 2.06 +/- 1.39 (+/- SD) for ectopic pregnancy and 1.91 +/- 0.81 for normal pregnancy (P greater than 0.05). The biological hCG to immunoreactive hCG beta ratios were 1.98 +/- 0.75 and 2.02 +/- 0.82, respectively. Serum hCG from both groups of women stimulated cAMP generation by testicular cells similarly. We conclude that the lower serum steroid levels in women with ectopic pregnancy cannot be explained by altered hCG bioactivity. The lower steroid levels may thus reflect a primary defect of the corpus luteum, absence of another stimulator of ovarian steroid biosynthesis, or more subtle alterations in hCG glycosylation which are important in vivo but not assessed by the in vitro bioassay.

Enzyme immunoassay of oestrogen and progesterone receptors in uterine and intrauterine tissue during human pregnancy and labour.

Oestrogen and progesterone receptors were studied in the non-pregnant state, in early pregnancy and at term using monoclonal antibody enzyme immunoassays. Receptors for both steroids were found in tissues from non-pregnant patients and patients in early pregnancy. At term oestrogen receptors were undetectable in all tissues studied. Progesterone receptors were undetectable in chorion, amnion and placenta at term, while present in extremely low concentrations in decidua and myometrium.

Radioimmunoassay of serum ferritin.

Purified human spleen ferritin was labelled with 125I. On Sepharose 6-B gel filtration four species of labelled products were separated: a component with a higher molecular weight than ferritin; a component which is eluted in the same volume as unlabelled ferritin; and two labelled compounds with molecular weights lower than ferritin. When these labelled materials were used in a double antibody radioimmunoassay, the high molecular weight fraction showed variable and high non-specific binding and was poorly displaced by unlabelled ferritin; the fraction behaving like true ferritin gave good standard curves and showed non-specific binding of less than 1%. The remaining two components showed poor binding to rabbit antiferritin. Using labelled material from the second fraction, a double antibody radioimmunoassay capable of measuring 2 microgram ferritin protein/litre of serum was developed. Inter- and intra-assay variation was between 3% and 8% over a concentration range of 0 to 250 microgram ferritin protein/litre. Good agreement between serum ferritin levels assayed by the present method and by an immunoradiometric method was obtained. Labelled ferritin was stable for at least six weeks. The simplicity of the methodology makes it possible to assay serum ferritin in large batches.

Blood or urine measurement of human chorionic gonadotropin for detection of ectopic pregnancy? A comparative study of quantitative and qualitative methods in both fluids.

One hundred seventy-five patients with features of ectopic pregnancy were studied, of whom 95 were subsequently shown to have an ectopic pregnancy. Paired blood and urine samples were assayed for human chorionic gonadotropin (hCG) by two radioimmunoassays, one immunoradiometric assay for intact hCG and an immunoradiometric assay for free beta subunit that also detects the "beta core" of hCG in urine. Qualitative testing was also performed using the Tandem Icon method of immunoconcentration on a membrane. The quantitative results for intact hCG showed an approximately unitary relationship between concentrations in both fluids, with a close correlation (r = 0.84, gradient = 1.01). The qualitative tests for hCG in both serum and urine were positive in all patients with ectopic pregnancy. The Tandem Icon is equally useful in blood and urine, whereas quantitative assays are more reliable in the blood. Quantitation of urinary hCG is not recommended because of the variable dilution of the glycoprotein in this fluid.

Changes in amniotic fluid prostaglandins with oxytocin-induced labor.

Amniotic fluid prostaglandin levels were measured serially in 15 patients who underwent successful induction of labor and compared with those of patients presenting in spontaneous labor. At comparable cervical dilation the induced group demonstrated significantly lower prostaglandin levels. Four of these patients delivered without any increment in prostaglandins while in the remaining patients increases in prostaglandins followed the attainment of efficient uterine contractions by several hours. These data support the hypothesis that oxytocin acts directly on myometrial cells and not primarily by prior generation of prostaglandin synthesis in the membranes.

Pituitary function in Sheehan's syndrome.

The responses of plasma prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone were measured in ten women with Sheehan's syndrome after intravenous administration of the appropriate releasing hormones. Growth hormone and cortisol responses to insulin-induced hypoglycemia were also measured. It was found that two patients were biochemically borderline euthyroid and eight were probably hypothyroid in the face of thyroid-stimulating hormone values in the reference range; in two patients thyroid-stimulating hormone response to thyrotropin-releasing hormone was appropriate. In no patient were the minimum prolactin levels achieved, in response to thyroid-releasing hormone as established in reference subjects. Growth hormone response to hypoglycemia was inadequate in all patients and only one patient achieved reference range values of cortisol during hypoglycemia. In six patients fasting LH and FSH were in the reference range and the response to gonadotropin-releasing hormone was adequate and appropriate in eight patients. In light of these findings it is suggested that prolactin response to thyrotropin-releasing hormone administration would be a reliable and simple screening procedure for suspected Sheehan's syndrome.

Serum progesterone in the diagnosis of ectopic pregnancy: a valuable diagnostic test?

The value of a single serum progesterone (P) assay in the diagnostic work-up of suspected ectopic pregnancy was investigated in 89 patients with ectopic pregnancy and 27 patients with incomplete abortion. Reference values for P in the blood were obtained from 77 patients with normal intrauterine pregnancies in the first trimester. With the use of a discriminatory level of 63 nmol/l (20 ng/ml), sensitivity of 92%, specificity of 84%, positive predictive index of 90%, and negative predictive index of 87% were achieved. Addition of pelvic ultrasound further improved the diagnostic accuracy. It is concluded that serum P measurement offers a valuable adjunct to existing methods of diagnosis of ectopic pregnancy.

Detection of urinary human chorionic gonadotropin by rapid immunoconcentration method is the first-line test for suspected ectopic pregnancy.

Nine hundred nine patients with suspected ectopic pregnancy were tested for human chorionic gonadotropin (hCG) using two qualitative assays: the Tandem Icon urine assay (Hybritech, San Diego, CA) and a serum radioimmunoassay (RIA) employing a positive cut-off of 25 IU/l. Pregnancy status was determined by clinical or histologic examination, or detection of hCG or its metabolites in four quantitative immunoassays: two RIAs and two immunoradiometric assays (IRMAs). Both the Tandem Icon and the qualitative RIA detected all 71 patients with ectopic pregnancy. The predictive indices of the Icon were 100% for a positive result and 99.6% for a negative result, and those of the RIA were 96.7 and 99.6%, respectively. The Tandem Icon thus fulfils the need for a simple, rapid, and sensitive method for hCG in the detection of patients with suspected ectopic pregnancy.

Male transmission of the gene for isolated gonadotropin-releasing hormone deficiency.

Three black women, daughters of the same father but three unrelated mothers, presented with isolated gonadotropin deficiency (IGD). Clinically, the patients had no midline defects and intact smell and taste senses. Biochemically, the essential feature was very low unstimulated and stimulated follicle-stimulating hormone and luteinizing hormone levels, even after priming with gonadotropin-releasing hormone over a 5-day period. Growth hormone response to insulin-induced hypoglycemia was somewhat blunted, but prolactin, cortisol, and thyroid-stimulating hormone responses were quite normal. All three patients had the 46,XX karyotype; clinical or biochemical aberrations could not be demonstrated in any of the remaining family members. The disorder was, apparently, transmitted by the deceased father, who manifestly did not have an IGD deficiency nor any of the midline stigmata associated with IGD. The mode of inheritance seems most likely to be autosomal dominant with variable penetrance.

Bedside application of an ultrasensitive urine test for HCG in patients with suspected ectopic pregnancy.

One hundred and seven patients with suspected ectopic pregnancy were tested for HCG at the bedside using the Tandem Icon. The test was performed by ward doctors with no formal laboratory experience. The patients were managed conservatively or by surgery as dictated by the clinical picture and the Icon test result. Retrospective categorisation of the 107 patients by laboratory analysis and clinical outcome showed that 21 were pregnant (17 ectopic, 4 intrauterine) and 86 non-pregnant. At the bedside the Icon was reported as negative in one pregnant patient and three patients who were not pregnant were found to give Icon-positive results. In the laboratory the Icon correctly categorised all patients. Three of the four discrepant results were found to be a direct result of the operator's inexperience in analytical procedure and interpretation. The Tandem Icon HCG urine assay can reliably be used at the bedside of patients with suspected ectopic pregnancy provided that the operator has had sufficient experience in its use.

Prolactin secretion in Sheehan's syndrome. Responses to thyrotropin-releasing hormone and metoclopramide.

The prolactin response to thyrotropin-releasing hormone (TRH) and metoclopramide was studied in 16 patients with Sheehan's syndrome and 16 matched controls in the follicular phase. Metoclopramide resulted in a greater prolactin response than TRH did in the controls. However, both stimuli failed to evoke any appreciable prolactin response in the patients with Sheehan's syndrome. Since metoclopramide is generally free of side effects and far cheaper than TRH, we recommend the prolactin response to metoclopramide as the preferred screening test in the diagnosis of Sheehan's syndrome.