William D. Odell

Infertility caused by bilateral testicular masses secondary to congenital adrenal hyperplasia (21-hydroxylase deficiency)

Two male cousins with partial 21-hydroxylase deficiency presented with bilateral testicular masses and infertility. In both cases, the testicular masses, consisting of adrenocorticotropic hormone-dependent pluripotential cells, were thought to play a major etiologic role in infertility. The administration of very small doses of dexamethasone, given at 11:00 P.M., led to the disappearance of the masses and a subsequent return of fertility. Although 21-hydroxylase deficiency is not by itself an uncommon condition, the presentation of testicular masses with subsequent reversible infertility in two family members with this condition has not previously been described.

Enhanced transdermal delivery of testosterone : a new physiological approach for androgen replacement in hypogonadal men

Abstract This report describes the rationale, development and initial clinical testing of a new modality for the treatment of hypogonadal men — an enhanced transdermal delivery system (TDS) for administering native testosterone. In contrast to the experimental trans-scrotal testosterone patches, the enhanced testosterone TDS can be applied to non-scrotal skin sites, such as the back, chest, arms, etc. A one-month pilot study in six hypogonadal men shows that the nightly application of two patches (for 24 h) delivers ~ 4 to 7 mg of testosterone per day, and produces testosterone plasma levels that closely mimic the magnitude and time course of the normal circadian rhythm seen in healthy young men. Moreover, the enhanced delivery of testosterone across non-scrotal skin, is not associated with any appreciable degree of transdermal first-pass metabolism, and therefore produces physiological levels and patterns of dihydrotestosterone (DHT) and estradiol (E 2 ). In all but one subject, skin tolerability has been acceptable. During 7 months of treatment in two patients, hormone levels have remained within the normal range, tolerability has been good, and subjective improvements in sexual function and well being have been reported. In comparison to other available methods of androgen replacement therapy (i.e. testosterone-ester injections, synthetic oral agents and testosterone pellet implants), we believe that the enhanced transdermal delivery of native testosterone promises to be a more physiological and patient-friendly approach for the treatment of hypogonadal men.

Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing's syndrome. Case report and review of the literature.

Non-iatrogenic Cushings syndrome has been associated primarily with three entities: pituitary-dependent processes due to pituitary adenomas or microadenomas causing adrenal hyperplasia; pituitary-independent primary adrenal causes, predominantly unilateral adenomas, rarely multiple adenomas or adrenal carcinoma; ectopic sources of adrenocorticotropic hormone (ACTH) production. Although non-neoplastic bilateral adrenal disease generally has been ascribed to extra-adrenal stimulation, a rare cause of Cushings syndrome that involves bilateral adrenal nodule formation independent of pituitary stimulation has been identified. Nodular adrenal diseases represent a confusion of terms in the literature, but one subgroup of Cushings syndrome has most frequently--and, perhaps, most appropriately--been designated primary adrenocortical nodular dysplasia. A case of this unusual entity is presented, and previous case reports pertaining to this confusing area of adrenal hyperfunction are reviewed. The characteristic manifestations that separate this diagnosis from other types of nodular adrenal disease are also discussed. Recognition of this diagnosis, although rare, is important, as bilateral adrenalectomy in the treatment of choice.

Identification of LH/hCG Receptors in Rabbit Uterus

Abstract Luteinizing hormone (LH) is believed to act via specific receptors to control gonadal steroidogenesis and reproductive processes. Recently A. J. Ziecik, P. D. Stanchev, and J. E. Tilton (Endocrinology 119:1159, 1986) reported surprisingly that LH/hCG receptors were present in porcine uterus, a tissue not known to be a target for LH action. We report herein the identification of high-affinity LH receptors in the rabbit uterus. Uteri from adult New Zealand white rabbits were homogenized in Tris-HCl, 0.25 M sucrose. After Alteration and sequential centrifugation, a partially purified pellet containing receptors was obtained. This preparation was incubated with a trace (1300 cpm) (50 pg) 125I-labeled chorionic gonadotropin and with various unlabeled protein hormones. Receptor bound was separated from free hormone by centrifugation at 1000g. Affinity was estimated by Woolf plot analysis. Specific binding sites for LH/hCG were identified. The following Kd s were calculated: human LH, 1.6 × 10-18; hCG, 0.5 × 10-11; human TSH, 1.3 × 10-9; and human FSH, 7.85 × 10-9. The reaction of human FSH and TSH with the receptor is best explained by LH contamination of these hormones. A similar preparation of rat liver showed that no binding sites were present. Rabbit ovarian LH receptors had a Kd slightly higher at 4.1 × 10-11 than that of the uterine LH receptors. Rabbit ovarian receptors were present at 2.27 × 10-13 M/mg protein compared to uterine receptors at 4.65 × 10-15 M/mg protein. We conclude specific- and high-affinity binding sites (receptors) for LH are present in the rabbit uterus. The function of these receptors remains unknown.

Effect of short- and long-term dexamethasone on 3α-androstanediol glucuronide in hirsute women *

The role of glucocorticoid therapy in regulating plasma 3α-androstanediol glucuronide (3α-diol G) content, a marker of androgen action, in hirsute women was unclear. A pulse injection of adrenocorticotropic hormone (0.5 U) following 1mg of dexamethasone (DEX) at midnight significantly increased the plasma level of cortisol CP P 4 -androstenedione (Δ 4 A), testosterone, dehydroepiandrosterone sulfate (DHEA-S), and 3α-diol G. Human chorionic gonadotropin administered for 3 days produced a significant ( P 4 A, DHEA-S, and 3α-diol G were suppressed ( P

Unusual cause of short stature.

A 24-year-old man evaluated for paresthesias and short stature was found to be hypocalcemic on initial presentation. Further evaluation showed that he had a low-normal parathormone level by amino-terminal assay, medullary stenosis of the long bones, and multiple ophthalmologic abnormalities. The remainder of his pituitary function, including growth hormone response to insulin-induced hypoglycemia, was normal. As no family history of similar findings was evident, a sporadic case of Kennys or Kenny-Caffey syndrome was diagnosed. He became normocalcemic in response to vitamin D and calcium carbonate therapy. The results of testing in this patient and the findings in other patients previously described with the Kenny-Caffey syndrome are reviewed.

Characterization and Purification of the Chorionic Gonadotropin-Like Protein Binding Site In Candida Albicans

Recent studies from our laboratory have shown that human chorionic gonadotropin (hCG), human luteinizing hormone (hLH), and CG-like proteins from Xanthomonas maltophilia (xCG) and Candida albicans (CaCGLP) induce Candida albicans transition from blastospores to hyphal forms. Xanthomonas maltophilia CG-like protein (xCG), hCG, and hLH also bind to Candida albicans blastospores with a high-affinity nM Kd, indicating that these substances can control Candida albicans pathogenicity. The work reported herein describes the purification of the binding site for these CG-like proteins from Candida albicans. The purification developed involved alcohol extraction followed by affinity chromatography. The product obtained was a protein of 64-69 kDa, as analyzed by sodium dodecyl sulfate-polyacrylamide electrophoresis (SDS-PAGE), Western blot and Sephadex G-100 column chromatography. This binding site reacted in a Western blot with both 125I-hCG and 125I-CaCGLP. Purified CaCGLP was able to displace specifically 125I-hCG bound to Candida albicans blastospores. Scatchard plot analysis showed that the Kd of this reaction was of high affinity in the nM range, and also indicated the presence of one single binding site. These results lead us to conclude: 1) Candida albicans possesses a binding site which is able to bind hCG, hLH and CG-like proteins from Xanthomonas maltophilia and Candida albicans; 2) This binding site is a hydrophobic protein of approximately 64 kDa and; 3) We postulate that CaCGLP is the natural ligand for this binding site and this system is used to control Candida albicans transition and, therefore, pathogenicity.

In vitro studies of prolactin inhibition of luteinizing hormone action on Leydig cells of rats and mice.

Abstract Previous in vivo studies have shown that in male rabbits prolactin inhibits the testosterone production stimulated by luteinizing hormone (LH) or human chorionic gonadotropin (hCG). This inhibition has now been studied in vitro using both mouse and rat testicular interstitial cells. First, the dose response of human LH (hLH) stimulation of testosterone was studied in detail using testicular interstitial cells from both species. Next, a small but stimulatory dose of hLH was selected and extensive prolactin doses were studied in vitro. NIH B-6 (bovine) prolactin in varying doses was added to the interstitial cells 30 min prior to the addition of a constant dose of hLH. Under these circumstances prolactin inhibited LH action over a wide range of doses. In both species a biphasic dose–response curve existed: large doses of 100 to 1000 ng/ml produced less inhibition or augmented LH action, compared to smaller doses. Next, entire hLH dose–response curves were produced in the presence of three doses of prolactin (0.33, 33, and 1000 ng/ml) as well as in the absence of prolactin. The addition of prolactin shifted the hLH dose-response curve to the right and depressed the maximal response in comparison to the curve without prolactin. Finally, inhibitory doses of prolactin resulted in no detectable change in LH receptor number as estimated from Scatchard plots. It is concluded that prolactin inhibits LH action on interstitial cells as determined by rate of testosterone production except at very large doses of prolactin where LH action is less inhibited or augmented. The inhibitory action of prolactin in this in vitro interstitial cell assay was not accompanied by a decrease in LH receptor number. Thus, a postreceptor action is likely to be involved.

PROLACTIN INHIBITION OF PREGNANT MARE'S SERUM STIMULATED FOLLICLE DEVELOPMENT IN THE RAT OVARY

Prolactin (PRL) effects on the female reproductive system have been presumed to occur primarily at the hypothalamic-pituitary level. The following studies were designed to evaluate whether PRL can directly alter gonadotropin actions at the ovarian level. In the first experiment, 10 groups of 7 cycling adult female rats were given a daily dose of pregnant mares serum (PMS: 25 IU) and either saline (SAL) or PRL (0.25, 0.8, 2.5, 8, or 25 micrograms) twice daily for 4 days. In the second experiment, PMS (6 doses: 0-75 IU/d; 16 animals/dose) was administered to all animals while half the animals at each PMS dose received PRL (25 micrograms twice daily) and half received an equal volume of diluent. Finally, hypophysectomized (hypox) adult rats (n = 5-6/group) received 25 IU PMS/d and PRL (0-75 micrograms) twice daily. An additional group received 0 PRL and 0 PMS. Ovarian weight and histology were evaluated at the completion of each study. In the first experiment, PRL inhibited PMS-stimulated ovarian weight gain in a dose-dependent manner (p less than 0.01). Numbers of preantral (p less than 0.005) and antral (p less than 0.05) follicles were decreased in animals receiving an inhibitory dose of PRL (25 micrograms BID) compared to controls. In the second experiment PRL (25 micrograms BID) again inhibited PMS-stimulated ovarian weight (p less than 0.01) at all doses of PMS. Finally, in hypox animals, PRL inhibited PMS-stimulated ovarian weight gain (25 and 75 micrograms PRL: p = 0.001), and mean number (p less than 0.001) and diameter (p less than 0.001) of antral ovarian follicles (8-75 micrograms PRL) compared to controls. In summary, administration of PRL inhibited PMS-stimulated ovarian weight gain, and antral follicle diameter (in hypox animals only) and number in adult female rats suggesting that in states of hyperprolactinemia, PRL alters gonadotropin-mediated activities (i.e., folliculogenesis) directly at the ovarian level in addition to its hypothalamic and pituitary actions.

Complete sequence of the gene encoding a chorionic gonadotropin-like protein from Xanthomonas maltophilia

Our laboratory has previously reported that: (i) Xanthomonas maltophilia (Xm) produces a protein which has immunological resemblance to the beta-subunit of human chorionic gonadotropin (hCG) and (ii) possesses a high-affinity receptor which binds holo hCG, and the endogenous ligand, Xm chorionic gonadotropin (xCG), but does not bind human luteinizing hormone (hLH). We have also previously published a 492-bp partial nucleotide sequence of the gene (xcg) coding for xCG. We report herein the entire xcg sequence of 1362 bp, which codes for a 48-kDa protein. This sequence confirmed the 492-bp sequence, as well as two partial amino acid (aa) sequences which we have previously reported. The sequence has a region which is homologous to aa 56-139 of the beta-subunit of hCG, and a second region homologous to the C-terminal tail of hCG. This is the first report of a prokaryotic gene homologous to the hCG beta-subunit-encoding gene.