Saul W. Rosen

Syndrome of Anosmia with Hypogonadotropic Hypogonadism (Kallmann Syndrome) Clinical and Laboratory Studies in 23 Cases

Abstract We have studied 23 patients (14 men, nine women) in 18 kindreds with anosmia and hypogonadotropic hypogonadism. Seven kindreds had more than one affected member, and included five eugonadal persons with anosmia and two eusomic women with hypogonadotropic hypogonadism. Other clinical abnormalities observed included: obesity (in nine), cryptorchidism (six), osteopenia (six), mild neurosensory hearing loss (five), gynecomastia (five), diabetes mellitus (four), cleft lip or palate or both (three), high-arched palate (two), short fourth metacarpal (two), and clinodactyly, camptodactyly, shortened frenulum of the tongue, multiple facial anomalies, right-sided aortic arch, malrotation of the gut, renal diverticulum, and mild red-green color blindness (one each). Normal secondary sex characteristics developed in all 20 patients treated on a long-term basis with chorionic gonadotropin or gonadal steroids. Responses to a single injection of gonadotropin-releasing hormone were heterogeneous. Five men had no luteinizing hormone response, five had a depressed response, and one an exaggerated response; two had no follicle-stimulating hormone response, five responses were depressed, three were normal, and one was ex-aggerated. None of seven women achieved a normal luteinizing hormone response to gonadotropin-releasing hormone; two had depressed follicle-stimulating hormone response, four responses were normal, and one was exaggerated. None of 11 patients tested responded to clomiphene. Two men fathered children. Each of two other men who underwent biopsy of the testes before and after long-term chorionic gonadotropin therapy showed mildly increased spermatogenesis. Little or no maturation beyond primordial follicles was observed in two ovarian biopsy specimens. Fifteen of 17 patients had normal basal prolactin levels and 14 of 16 had normal thyrotropin-releasing hormone-induced prolactin increase, but nine of 15 tested had a decreased or absent response of prolactin to chlorpromazine. Circulating concentrations of thyroid hormones were normal, but four of 17 patients tested had depressed TSH (thyroid-stimulating hormone) responses to thyrotropin-releasing hormone, and one man had an exaggerated response. Three of 12 patients had a depressed cortisol response to insulin-induced hypoglycemia, and two of seven patients had slightly depressed deoxycortisol responses to metyrapone. Growth hormone and vasopressin release in all 14 and all 12 patients, respectively, studied were essentially normal. Patients with anosmia and hypogonadotropic hypogonadism may have hypothalamic defect(s) responsible for the hypogonadotropism and perhaps for certain additional deficiencies of anterior pituitary function found in some. The cause of less frequent phenotypic abnormalities has not been established. In certain pedigrees, the evidence suggests that the major manifestations of the syndrome are inherited as an autosomal recessive trait.

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.

Ectopic gonadotropin production before clinical recognition of bronchogenic carcinoma.

GONADOTROPIN production by lung tumors has previously been found in men with well advanced carcinoma of the bronchus.1 , 2 In the following case the plasma had an increased concentration of gonadot...

Ovarian morphology in women with anosmia and hypogonadotropic hypogonadism

Ovarian biopsies from five women with the syndrome of hypogonadotropic hypogonadism and anosmia who had not previously received exogenous gonadotropins were evaluated with special emphasis on follicular morphology. Follicular development past the primordial stage was rarely observed, suggesting that early stages of follicular maturation require amounts of gonadotropins in excess of those secreted in these women.

The Syndrome of Basal Encephalocele and Hypothalamic-Pituitary Dysfunction

We documented hypothalamic-pituitary dysfunction in three patients with congenital herniation of the brain through the base of the skull (basal encephalocele). All had growth hormone deficiency, although one has attained normal height. One had diabetes insipidus. Two had hypogonadotropic hypogonadism. Prolactin secretion was elevated in one, normal in another, and borderline low in the third. Two patients were euthyroid, but in response to thyrotropin-releasing hormone (TRH) injection, one patients thyrotropin (TSH) level increased to levels exceeding normal while the others did not attain normal levels. In the third patient, TSH response to TRH went from subnormal to normal after treatment with growth hormone and thyroxine. No patient had evidence of ACTH deficiency. These heterogeneous findings do not permit assignment of an unequivocal anatomic or functional site to the endocrine defect(s). Pituitary function should be evaluated in all patients with basal encephalocele, and this entity should be considered in the differential diagnosis of central endocrine malfunction.

Gonadotropin-secreting renal carcinoma

Tumors of the kidney are known to cause an impressive array of extrarenal manifestations. A patient with a primary malignant renal tumor associated with the production of chorionic gonadotropin (hCG), placental lactogen, and placental alkaline phosphatase is described. The gonadotropic hormone was identified as hCG by a recently developed radioimmunoassay that distinguishes hCG from pituitary luteinizing hormone. This report establishes another humoral syndrome to be considered in association with renal tumors.

Human chorionic gonadotropin and human placental lactogen in extragonadal tumors an immunoperoxidase study of ten non-germ cell neoplasms

The immunoperoxidase localization of the alpha and beta subunits of human chorionic gonadotropin (hCG) and of human placental lactogen (hPL) was studied in ten extragonadal nontrophoblastic tumors associated with raised serum levels of one or more of these placental proteins. Three of the tumors were bronchial carcinomas, one was a gastric carcinoma, two were malignant carcinoids (one bronchial and one gastric), two were pancreatic islet cell carcinomas, and two were metastatic carcinomas with an unknown primary site. The maximum alpha subunit serum level was 33,000 ng/ml (gastric carcinoid), the maximum hCG/hCG‐beta level was 705,000 ng/ml, and the maximum hPL level was 50 ng/ml (both in the gastric carcinoma). An indirect immunoperoxidase technique and rabbit polyclonal affinity‐purified antibodies and peroxidase conjugates were used on formalin‐fixed, paraffin‐embedded sections. Five blocks (eight cases) or six blocks (two cases) from various sites were obtained from each patient at surgery and/or autopsy. Positive stains for hCG/hCG‐beta were seen in six of seven tumors (25/37 blocks) with raised levels, for the alpha subunit in nine of nine tumors (30/47 blocks), and for hPL in two of five tumors (4/26 blocks). Only a relatively minor number of the cells were positive, and within the same case, there was considerable site‐to‐site variation in the number of positive cells. Large bizarre cells contained hCG/hCG‐beta as well as the alpha subunit, if it was demonstrated in the same tumor as the beta subunit. Otherwise, the alpha subunit was found in small unremarkable cells. Giant cells that were smaller than those positive for hCG/hCG‐beta contained in hPL. In some serial sections, hCG‐alpha, hCG/hCG‐beta, and hPL were segregated in different cell populations, supporting the concepts of their separate genetic control.

Congenital Anosmia: Detection Thresholds for Seven Odorant Classes in Hypogonadal and Eugonadal Patients

Detection thresholds for a representative from each of seven odorant classes (putrid, pepperminty, ethereal, camphoraceous, pungent, musky, floral) were determined by double-blind smell testing of seven normal males, six normal females, 6 patients with uncomplicated congenital anosmia and 13 patients with the syndrome of congenital anosmia and hypogonadotropic hypogonadism (the Kallmann syndrome, olfactogenital dysplasia). The median detection thresholds did not differ significantly between hypogonadal and eugonadal anosmics for any of the odorants, suggesting that the endocrine deficit does not result from inadequate rhinencephalic input to brain centers controlling gonadotropin release. Phenylethylmethylethylcarbinol (PEMEC), a stable chemical of the floral class, was detected at very low concentrations (10−6 to 10−8 M in water) by all normals tested. Since no patient with congenital anosmia was able to distinguish even undiluted PEMEC from water, we suggest that this compound is the material of choice for convenient, rapid and objective testing of the sense of smell (cranial nerve I).

Enzymatic sulfation of steroids by bovine tissues

Abstract The synthesis of sulfate esters of dehydroepiandrosterone (DHA), estrone, testosterone, and p-nitrophenol by the supernatant fraction of various adult bovine tissue homogenates is reported. All tissues synthesized p-nitrophenyl sulfate. Synthesis of testosterone sulfate occurred only with liver. Estrone sulfate was formed by many tissues, but synthesis of DHA sulfate was limited to placenta, liver, adrenal gland, intestine, pituitary, kidney, and uterus. Bovine placenta was much more active than human placenta in the sulfation of these substrates.

Ectopic placental proteins in nontrophoblastic tumors. Serial measurements following chemotherapy

Four men with metastatic carcinoma (two bronchus, one stomach, one primary unknown) and ectopic placental protein production (one chorionic gonadotropin (hCG and its alpha subunit; one placental lactogen (hPL); one hCG alone; one hCG and hPL) were studied with serial retrospective measurements of the ectopic protein concentrations in serum, correlated with objective assessment of clinical status. The biochemical marker and clinical response were documented during treatment with a variety of agents and during periods without therapy. Of nine assessable periods, seven showed concordance of biochemical marker and clinical responses.