Antibody to human follicle-stimulating hormone: cross-reactivity with three other hormones.

Antibodies directed against human follicle-stimulating hormone (FSH) were demonstrated in rabbit serum by neutralization of biological activity. Antibodies that bound FSH-(131)I were produced in rabbits and guinea pigs by repeated injections of FSH. By (131)I immunochemical methods, we found that at least 90% of the FSH-(131)I-binding antibody failed to distinguish the four human glycoprotein hormones: FSH, luteinizing hormone, chorionic gonadotropin, and thyrotropin, purified as well as endogenous hormone in plasma. Neither growth hormone, adrenocorticotropin, nor a variety of glycoproteins or animal plasmas were able to react with these antibodies.

Ectopic production of the isolated beta subunit of human chorionic gonadotropin.

A material similar to the beta subunit of human chorionic gonadotropin (hCG-beta) was detected in serum (300 ng/ml) and tumor extract from a 75-yr-old man with pancreatic adenosquamous carcinoma. This material was indistinguishable from hCG-beta in three different types of radioimmunoassay that displayed widely varying reactions with glycoprotein trophic hormones and their subunits. In gel chromatography there appeared to be heterogeneity of the serum beta-like immunoactivity, including one component that coeluted with standard hCG-beta tracer and another immunologically indistinguishable component that displayed a slightly lower elution volume. Neither complete human chorionic gonadotropin (hCG) nor its alpha subunit was detected in radioimmunoassays of serum, before or after fractionation, or in tumor extract. The absence of complete hCG was confirmed in a gonadotropin bioassay sensitive to 15 ng of hCG, which showed no bioactivity in serum or tumor extract containing 450 and 90 ng of hCG-beta, respectively. This case probably represents the first demonstration of isolated polypeptide subunit production of ectopic origin and suggests that hCG-beta, as well as other subunits, may prove useful as cancer markers.

Differences between purified ectopic and normal alpha subnits of human glycoprotein hormones.

"Ectopic" proteins, not distinguished immunologically from the common alpha subunit of the human glycoprotein hormones, were purified approximately 10,000-fold from a gastric carcinoid tumor (A.L.-alpha) and from tissue culture medium of bronchogenic carcinoma cell lines (ChaGo-alpha). The purified A.L.-alpha was homogeneous by sodium dodecyl sulfate (SDS) gel electrophoresis while the purified ChaGo-alpha showed multiple components, some of which represented aggregated species. In SDS gel electrophoresis, the apparent molecular weights of A.L.-alpha (15,000) and dithioerythritol-reduced ChaGo-alpha (13,000) were significantly lower than those of the alpha subunits of human chorionic gonadotropin (hCG-alpha), luteinizing hormone, follicle-stimulating hormone, or thyroid-stimulating hormone (22,000-23,000). Binding experiments with [35S]-SDS suggested that these apparent differences in molecular weight resulted, at least in part, from diminished binding of the SDS by the normal compared to the ectopic alpha subunits. In gel chromatography, the apparent molecular weights of A.L.-alpha (27,000) and ChaGo-alpha (30,000) were slightly higher than those of normal alpha subunits (23,000-24,000). Both A.L.-alpha and ChaGo-alpha were not distinguished from hCG-alpha in ion-exchange chromatography. The composition of A.L.-alpha was similar to that of hCG-alpha in 13 amino acids but showed decreased phenylalanine and increased valine; glucosamine was identified in both A.L.-alpha and hCG-alpha. Under conditions in which hCG-alpha combined with the hCG beta subunit (hCG-beta) to produce 95% of the expected gonadotropin-binding activity in a rat testis radioreceptor-assay, A.L.-alpha incubation with hCG-beta resulted in only 2% of the expected activity, and ChaGo-alpha incubation with hCG-beta produced no detectable activity. These characteristics of ectopic alpha subunits may reflect abnormalities of neoplastic protein synthesis or carbohydrate attachment which result in polypeptides with chemical and immunologic similarity to normal subunits but with differences in physical and combining properties; alternatively, the ectopic subunits may represent as yet unrecognized alpha precursor forms.

Increased "pregnancy-specific" beta1-glycoprotein in certain nonseminomatous germ cell tumors.

Schwangerschafts (pregnancy) protein No. 1 (SP1), a recently identified beta1-glycoprotein that occurs during pregnancy, was assayed in the sera of 97 men with germ cell tumors of the testis. SP1 was elevated at 11-440 ng/ml in 3 of 6 men with choriocarcinomas, in 5 of 17 men with teratomas or "teratocarcinomas" (embryonal carcinomas and teratomas), and in 5 of 50 men with embryonal carcinomas; the highest value in 143 patients with nonmalignant diseases was 9.1 ng/ml. None of 24 sera from men with seminomas and none of 5 sera from men with orchitis had elevated SP1. In the 1 patient examined, testicular choriocarcinoma SP1 had immunochemical and gel chromatographic properties similar to those of highly purified SP1 of placental origin.

Use of circulating pregnancy-specific beta 1 glycoprotein as a marker in carcinoma of the breast in women.

Pregnancy-specific beta 1 glycoprotein (SP1) was determined by radioimmunoassay in sera from 27 normal women, 33 women with benign breast disease, and 191 women with carcinoma of the breast, staged for extent of the disease. All diagnostic groups exhibited substantial overlap in SP1 values. Those with benign breast diseases tended to have values at least as high as those with cancer. Normal patients tended to have slightly lower values, but this difference may well have been due to the younger ages of the normal patients in our sample, because SP1 values tended to increase with age. Immunochemical dilutions of SP1 in the serum with the highest value (10.2 ng/ml) did not differ significantly from standard placental SP1.

Influence of chemotherapeutic agents on chorionic gonadotropin-alpha subunit secretion in a human lung cancer cell line (ChaGo): discordance of cytotoxic and secretory effects.

Cells from cultures of ChaGo, a cell line of a human lung cancer that ectopically produces chorionic gonadotropin (hCG) and its alpha subunit (hCG-alpha) were exposed to five different cancer chemotherapeutic agents in vitro in separate experiments (one drug/expt). The control doubling time averaged 4 days, with molar biphasic secretory rates of hCG-alpha ranging from a high of 58.1 to a low of 10.5 pmoles/10(6) cells/24 hours. Drug concentrations were chosen to induce a 30-60% inhibition of cell replication over a period of 8-10 days. Neither methotrexate nor vincristine demonstrated major effects on extracellular hCG-alpha production, but each agent moderately depressed cell number and each produced major inhibition of intracellular protein synthesis. Procarbazine inhibited marker production only in slight excess of inhibition of cell growth and cell protein. Actinomycin D and mechlorethamine, however, had profound effects on inhibition of hCG-alpha production in excess of cell growth. Our results indicated that cancer chemotherapeutic agents have specific and differing effects on cell growth and cell protein on the one hand and marker production on the other. These data suggested a mechanism for certain cases of discordance between hormone production and clinical status.

Ultrastructural concomitants of sodium butyrate-enhanced ectopic production of chorionic gonadotropin and its alpha subunit human bronchogenic carcinoma (ChaGo) cells.

Sodium butyrate treatment of cultures of ChaGo (human lung cancer) cells resulted in increased production of human chorionic gonadotropin (hCG) and its alpha subunit (hCG-alpha) and induced a variety of morphologic changes. Elongation and flattening of cells were seen by light microscopy. Immunocytochemistry with antisera against hCG and against hCG-alpha showed an increase in cells containing stainable hCG-alpha. Scanning electron microscopy demonstrated enhanced adhesion of cells to glass cover slips, with elongation, flattening, and decreased cytoplasmic blebs. Ultrastructural changes were examined by transmission electron microscopy and evaluated quantitatively by an unbiased observer. Significant findings included increases in perinuclear tonofilaments, smooth endoplasmic reticulum vesicles, dense mitochondrial inclusions, and lipid granules, as well as decreases in intercellular desmosomes, free polyribosomes, mitochondrial dense granules, and Golgi complexes. The most notable change, a marked decrease in condensed chromatin clumps, may have reflected a butyrate-induced biochemical modification of chromatin leading to enhanced accessibility of certain genes for transcription.

Expression of oncodevelopmental gene products by human tumor cells in culture.

Sixty-seven human tumor cell lines and 15 lines derived from normal tissue were examined for the production of the oncodevelopmental markers carcinoembryonic antigen, alpha and beta subunits of chorionic gonadotropin, placental and nonplacental forms of alkaline phosphatase, gamma-glutamyltransferase, cystyl aminopeptidase, and calcitonin. Both intracellular and extracellular levels of these markers were determined at three phases during the growth of each culture. Sixty-eight percent of the cell lines produced elevated levels (greater than or equal to 90th percentile) of at least one marker. Of those, 46% produced elevated levels of one marked only, 29% produced two, 22% produced three, and 4% produced four markers. No cell line produced more than four markers at elevated levels. In most instances, however, the expression of any two particular markers was discordant. For approximately 50% of the possible marker pairs, Spearman rank-ordered correlation analyses showed significant negative correlations, indicating that when one marker was produced at elevated levels by a given cell line, other markers were usually absent ot produced at relatively low levels. In no instance was a significant positive correlation found between two markers. These data indicated that, although most human malignant cells examined produced one or more oncodevelopmental gene markers at elevated levels, no predictable coexpression of any two of the markers was seen.

Ectopic and eutopic secretion of chorionic gonadotropin and its sub-nits in vitro: comparison of clonal strains from carcinomas of lung and placenta.

We compared rates of secretion in vitro of human chorionic gonadotropin (HCG) and its subunits alpha and beta by established clonal cell lines of a bronchogenic carcinoma (ChaGo) and a choriocarcinoma (JEG). Clones showing the highest secretion rates of either HCG or its subunits were studied: ChaGo-K1, a new clonal strain, and ChaGo-C5 and JEG-3, two previously reported clonal lines. Cells were grown under identical conditions in the same laboratory. Hormone and subunit concentrations were measured by radioimmunoassays. ChaGo-K1 and ChaGo-C5 secreted only alpha-subunit whereas JEG-3 secreted only HCG. Average peak secretion rates in picomoles/day/mg protein were: for ChaGo-K1, HCG less than 0.3, alpha=290, and beta less than 0.5; for ChaGo-C5, HCG less than 0.3, alpha=21, and beta less than 0.5; and for JEG-3, HCG=18, alpha less than 0.7, and beta less than 0.5. The ChaGo-K1 secretion rate of alpha was greater than that of any of out previously reported ChaGo clones. Significant quantities of estradiol and progesterone accumulated in the media of all three cell lines; however, only JEG-3 secreted detectable quantities of placental lactogen. Thus under identical culture conditions, a bronchogenic carcinoma clonal line secreted only alpha-subunit, whereas a choriocarcinoma line secreted only HCG; these findings implied major differences in cellular control mechanisms. Moreover, the ectopic secretions of alpha exceeded the eutopic trophoblastic secretion of HCG, which suggested that in certain cases ectopic protein production may be even more efficient than nonectopic production.

Maintenance of ectopic chorionic gonadotropin and alpha subunit secretion by a human lung cancer cell line (ChaGo) transplanted into nude mice.

ChaGo cells, derived from a human primary carcinoma of the lung, were successfully transplanted into nude mice without any change in morphologic characteristics over four generations and with continued ectopic secretion of human chorionic gonadotropin (HCG) and HCG alpha subunit (HCG-alpha). The concentration of free HCG-alpha was 1,100-fold higher than that of complete HCG in the original ChaGo culture medium but only 35-fold higher in nude mouse plasma, possibly due to slower metabolic clearance of complete HCG. Tumor weights correlated with plasma HCG-alpha but not with HCG. Tumor-bearing mice had significantly heavier uteri than did control mice.

Stimulation of N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate of ectopic production of the free beta subunit of chorionic gonadotropin by a human brain tumor cell line.

Previous studies have favored a basic difference in the regulation of specialized protein production by cells derived from the usual tissue of origin (eutopic) and cancer cells derived from a tissue not normally producing the protein (ectopic). Thus N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate was believed to stimulate only eutopic (but not ectopic) chorionic gonadotropin production, and butyrate to stimulate only ectopic (but not eutopic). However, in CBT, a human brain tumor cell line, we find that N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate, but not butyrate, stimulated ectopic production of the beta subunit of chorionic gonadotropin. We conclude that neither butyrate nor cyclic adenosine 3':5'-monophosphate derivatives reliably discriminate ectopic from eutopic regulation.

A distinctive form of human chorionic gonadotropin beta-subunit-like material produced by cervical carcinoma cells.

The DoT and CaSki human cervical carcinoma cell lines ectopically produce material immunologically similar to the beta-subunit of human chorionic gonadotropin (hCG beta). Culture fluids were analyzed by gel filtration chromatography and radioimmunoassay (RIA) using (a) antiserum directed to conformation-specific (core-directed) determinants not involving the carboxyl-terminal peptide (CTP) in hCG beta purified from urinary hCG (i.e., standard hCG beta) or (b) antiserum directed to the CTP in standard hCG beta. CTP-directed RIA recognized a peak of hCG beta-like immunoreactive material that eluted in the same position as standard hCG beta. However, core-directed RIA recognized additional hCG beta-like material (i.e., ectopic beta-II), most of which eluted before standard hCG beta. CaSki cells were incubated with [3H]mannose, [3H]proline, and [3H] leucine, and the spent medium was immunoprecipitated and analyzed by gel electrophoresis. Several labeled peaks were detected in the lane from the anti-hCG beta X Sepharose immunoprecipitate, one of which corresponded in mobility to standard hCG beta, with two more intense components migrating at higher apparent molecular weights. Carboxypeptidase Y digestion released only 0.2 mol equivalents each of [3H]proline and [3H]leucine from the labeled CaSki material immunoprecipitated with anti-hCG beta X Sepharose, compared to 1 mol equivalent each in similar analysis of standard hCG beta. These findings were consistent with the absence of the 4-carboxy-terminal amino acids from 80% of the hCG beta-like immunoreactive material secreted by CaSki cells. The affinity purified ectopic beta-II failed to combine with standard hCG alpha under conditions in which combination of standard hCG beta with standard hCG alpha was essentially complete. Neither aggregation nor proteolytic degradation was the cause of failure of ectopic beta-II to combine with hCG alpha. We conclude that both the DoT and CaSki cervical carcinoma cell lines secrete a distinctive form of hCG beta-like material, ectopic beta-II. Lack of recognition by CTP-directed antisera and amino acid analysis suggest that ectopic beta-II may lack the CTP, despite its apparent larger size relative to standard hCG beta.

Myeloproliferative syndrome evolving in a patient with macromolecular lactate dehydrogenase.

A myeloproliferative syndrome, masked by severe iron deficiency, evolved in a woman with lactate dehydrogenase (LDH) complexed to IgA. Macromolecular LDH is an uncommon cause of increased serum LDH activity. By observing the patient's course for ten years, we were able to understand the initially puzzling clinical findings.

POEMS syndrome: studies in a patient with an IgG-kappa M protein but no polyneuropathy.

A 48-year-old woman had a variation of the syndrome of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (the so-called POEMS syndrome). The patient's neurological findings were entirely normal, but she had splenomegaly, hyperprolactinemia with galactorrhea and oligomenorrhea, a thyroid nodule with evidence of mild thyroiditis on aspiration biopsy specimen, and IgG-kappa monoclonal gammopathy, and hyperpigmentation and thickening of the skin. A short course of plasmapheresis (twelve 4-L exchanges in one month) did not alter any of the clinical abnormalities, but did result in a 70% decrease in the monoclonal IgG level (from 2.2 to 0.7 g/dl).

Differences in the carbohydrate moieties of the common alpha-subunits of human chorionic gonadotropin, luteinizing hormone, follicle-stimulating hormone, and thyrotropin: preliminary structural inferences from direct methylation analysis.

The carbohydrate components of combined alpha-subunits of urinary hCG and human pituitary LH (hLH), FSH (hFSH), and TSH (hTSH), each derived from the intact hormone, were studied by direct sugar analysis and methylation analysis. The methods provide a complete survey of the structural elements contained in the complex sugars associated with these glycoproteins, but do not establish the sugar sequences or anomeric configurations of glycosidic bonds. By analogy to N-linked oligosaccharides that occur in many glycoproteins, the data suggest distinct structural features for carbohydrates of alpha-subunits combined with beta-subunits. hCG alpha contains biantennary asparagine-linked chains terminated by either NeuAc alpha 2-3Gal beta 1- or GlcNAc beta 1-2 Man alpha 1- and lacks fucose. hTSH alpha contains biantennary chains with the same termini as hCG alpha plus terminal R-O-4GalNAc and a fucosyl residue linked alpha 1-6 to the inner GlcNAc residue of the N-linked chitobiosyl core. hLH alpha may contain some high mannose chains, but primarily contains biantennary chains terminated by NeuAc alpha 2-3(6)Gal beta 1-, GlcNAc beta 1-, GalNac-1-, R'-O-6GlcNAc-1-, and R"-0-2Man-1-plus a fucosyl residue linked alpha 1-6 to the inner GlcNAc residue of the N-linked chitobiosyl core. hFSH alpha contains more complicated structures that probably include a bisecting GlcNAc residue linked beta 1-4 to a 3,6-di-O-substituted core mannosyl residue, and terminal NeuAc alpha 2-3Gal beta 1-4(+/- Fuc alpha 1-3)GlcNAc-1, Gal beta 1-4(+/- Fuc alpha 1-3)GlcNAc-1-, R"'-O-GalNAc-1-, and GalNAc-1. In addition, the presence of 2,4-di-O-substituted mannose in hFSH alpha indicates that it contains triantennary chains. The identities of the R; R', R", and R"' groups were not determined, but recent studies of glycoprotein hormones suggest that they may be sulfate groups. Our results demonstrate differential glycosylation of virtually identical polypeptide hormone alpha-subunits produced in the same organ or perhaps even in the same cell.

De novo synthesis and secretion of heterogeneous forms of human chorionic gonadotropin and its free alpha-subunit in the human choriocarcinoma clonal cell line JEG-3.

The clonal human choriocarcinoma cell line JEG-3 secretes hCG and heterogeneous forms of its free alpha-subunit. We have studied the relationship of these forms in de novo biosynthesis experiments. Cells at near confluence were labeled with [35S]methionine by continuous (10-min to 24-h exposure) and by pulse-chase (5-min exposure, 10-min to 4-h chase) techniques. Media and cell lysates, chromatographed in Sephadex G-100 or, after reduction, electrophoresed on 12-20% gradient sodium dodecyl sulfate-polyacrylamide slab gels (SDS-PAG:), were analyzed by immunoprecipitation with antisera to hCT-alpha and hCG-beta. The intracellular labeled free alpha-subunit observed in lysates at all time points of either continuous or pulse-chase experiments was the same size or was slightly smaller on G-100 (apparent mol wt, 21,600 +/- 3,900) than urinary standard alpha-subunit (CR119 alpha; apparent mol wt, 22,700 +/- 1,500) and also somewhat smaller on SDS-PAGE (apparent mol wt, 19,400 +/- 600) than urinary standard alpha-subunit (apparent mol wt, 20,200 +/- 1,100). However, the predominant form of secreted free alpha-subunit, at chase times as early as 30 min, migrated with a higher apparent molecular weight in both systems (SDS-PAGE, 22,100 +/- 400; G-100, 29,300 +/- 2,700). We have not observed this secreted large free alpha-subunit in the cell lysate, and our data suggest that the small intracellular alpha-subunit is a precursor of the larger secreted alpha-subunit and not vice versa. The beta-subunit of secreted hCG was somewhat larger (apparent mol wt, 31,500 +/- 1,000) on SDS-PAGE than standard beta-subunit (CR119-2 beta and CR115 beta; apparent mol wt, 29,900 +/- 1,900). Secreted intact hCG migrated with urinary standard hCG (CR119) on G-100, but analysis of 35S-labeled intracellular hCG was complicated by co-precipitating large mol wt proteins. De novo synthesis and secretion of a large form of free alpha-subunit as well as a large beta-subunit in hCG may be due to posttranslational oligosaccharide addition during the secretory process.

Synthesis of chorionic gonadotropin subunits in human choriocarcinoma clonal cell line JEG-3: carbohydrate differences in glycopeptides from free and combined alpha-subunits.

The glycoprotein hormone hCG and its free alpha-subunit are secreted by the clonal choriocarcinoma cell line JEG-3. Free hCG alpha has a larger apparent mol wt (22,000-24,000) than the combined hCG alpha (18,000-19,000) obtained by dissociation of the hCG secreted by these cells. Techniques developed for the specific isolation and purification of the free and combined hCG alpha forms and for the preparation of glycopeptides from these subunits have permitted detection of the incorporation of D-[3H]glucosamine [( 3H]GlcN) and L-[3H]fucose into both alpha-subunit forms. Relative to their [35S]methionine content, 2.3-fold more [3H]GlcN and 6-fold more L-[3H]fucose were incorporated into free hCG alpha than into combined hCG alpha. Analyses of [3H]GlcN glycopeptides prepared from free and combined hCG alpha indicate that the 22,000- to 24,000-dalton subunit form contained more [3H]GlcN and 27% more of the GlcN metabolite N-acetylneuraminic acid than the 18,000- to 19,000-dalton hCG alpha-subunit, than both hCG alpha forms contained two major N-linked oligosaccharide chains differing primarily in their NeuAc content, and that most of the [3H]GlcN was incorporated as GlcN or metabolites of GlcN other than N-acetylneuraminic acid. These studies provide direct chemical evidence of a higher content of carbohydrate in the larger free alpha-subunit form.

Production of pregnancy-specific beta 1-glycoprotein by cultured placental cells.

The synthesis of pregnancy-specific beta 1-glycoprotein (PS beta G) was studied in simian virus 40 temperature-sensitive A mutant-transformed human first trimester and term placental cells. At the permissive temperature (33 C, transformed phenotype), they produced low levels of PS beta G. At the restrictive temperature (40 C), the transformed phenotype was lost, and the production of PS beta G was greatly enhanced. The PS beta G produced by these transformed placental cells resembled the purified placental PS beta G by several criteria. Both cell and placental PS beta G bound to Concanavalin A-Sepharose and were, therefore, glycoproteins. The cell PS beta G cochromatographed with placental PS beta G on a Bio-Gel A-0.5m column. Furthermore, the slopes of the dose-response curves for the cell PS beta G were indistinguishable from that for placental PS beta G. The synthesis of PS beta G at both 33 and 40 C in these placental cells was greatly induced by sodium butyrate and 5-bromo-2'-deoxyuridine. Sodium butyrate was a more effective inducer at 33 C, whereas BrdUrd appeared to be a better inducer at 40 C.

Increased glycosylation of serum human chorionic gonadotropin and subunits from eutopic and ectopic sources: comparison with placental and urinary forms.

The role of carbohydrate in the heterogeneity of hCG and its subunits is unclear. To study this question, we chromatographed over Sephadex G-100 an extract of term placenta as well as sera from a woman in the first and third trimesters of pregnancy and sera from two patients with nontrophoblastic malignancies. Samples were cochromatographed with radiolabeled urinary standards. hCG from first trimester pregnancy serum showed multiple peaks on G-100. The dominant peak eluted with an apparent molecular weight (72,000) higher than that of hCG from third trimester serum (63,000), urine (6),000), and placenta (59,000). hCG from both malignancy sera eluted with an apparent molecular weight (62,000) similar to that of hCG from third trimester and urinary hCG. Free hCG alpha from all sera eluted with a similar apparent molecular weight (29,000), which was higher than that of placental and urinary free alpha-subunit (22,000) and the alpha-subunit dissociated from intact hCG from all sources (22,000--23,000). The subunits were dissociated in the denaturing medium of 6 M guanidine-HCl, pH 3.0, and chromatographed in this medium over Sepharose CL-6B. This eliminated all of the differences in apparent molecular weight among corresponding forms that were found on G-100. All forms of hCG alpha coeluted with a chemically identified 80% deglycosylated hCG alpha. hCG and free alpha-subunits were incubated with mixed exoglycosidases which lacked detectable protease activity and were then rechromatographed on G-100. After deglycosylation, hCG from different sources eluted with a considerable heterogeneity (mol wt range, 40,000--50,000) not present in the native forms. Despite the heterogeneity of native free alpha-subunit from various sources, deglycosylation produced a common species with apparent molecular weights of 11,000--12,000, close to the chemically determined molecular weight of the polypeptide chain (10,400). These studies suggest that1) ectopic serum hCG and free alpha-subunit are similar to corresponding eutopic forms; 2) serum hCG and free alpha-subunit from all sources are more glycosylated than placental or urinary forms; 3) first trimester hCG is more glycosylated than other forms of hCG; and 4) serum free alpha-subunit is more glycosylated than the alpha-subunit which combines with hCG beta to form intact hCG.

Comparison of the effects of lung cancer, benign lung disease, and normal aging on pituitary-gonadal function in men.

We retrospectively determined serum total testosterone (T), fraction of T bound, free T index, LH, and FSH levels in 122 men with malignant lung disease, 32 men with benign lung disease, and 106 normal men. Men with malignant and, to a lesser extent, benign lung disease had decreased serum total T and free T index values at the 5th percentiles, with elevations of LH and FSH levels at the 95th percentiles. Linear regression analysis showed reductions in total T and free T index and increases in FSH, but not LH, levels with age in each group. Using multivariate analysis, we found stronger independent effects of disease than age on serum total T and fraction of T bound, but a greater influence of age on free T index. Serum LH values differed by diagnosis, whereas FSH differed by age. Relative to values in the normal men, mean serum total T levels were reduced in men with lung cancer; the fraction of T bound was decreased in the men with lung cancer and increased in the men with benign lung disease, the free T index was decreased in the men with both malignant and benign lung disease, and LH was increased in the men with lung cancer. The hormone and hormone binding results were similar in men with different types of lung cancer. Biochemical evidence of primary and secondary (or combined primary and secondary) hypogonadism was present in 50-59% and 28-32%, respectively, of the men with malignant and benign lung disease vs. 10% of the normal men. These data suggest that 1) there is an increased prevalence of both pituitary gonadotropic and testicular dysfunction in men with malignant and, to a lesser extent, benign chronic lung disease, and 2) the effects of illness are independent of, and quantitatively greater than, those due to age.