Harry E. Hadd

Androgen excretion patterns in a patient with a metastatic hilus cell tumor of the ovary

The second reported patient with a metastatic hilus cell tumor of the ovary is described. Testosterone sulfate excretion was magnified from normal by nearly 10,000 times. There is no other recorded instance of so large an increase of this hormone in any pathologic condition. Perhaps in those cases of undiagnosed hirsutism and/or masculinization, this solvolyzed fraction of testosterone may be a clue to the origin of the problem. This may be an extremely sensitive mirror to neoplastic processes, particularly on hormonally dependent tissues. There is every likelihood that this hormone conjugate was produced by the tumor cells and not just from the sulfurylation of the free testosterone.

Ethynylestradiol-17β D-ring glucuronide conjugates are potent cholestatic agents in the rat

17 alpha-Ethynylestradiol-17 beta (beta-D-glucuronide) [EE217 beta (beta G)], a metabolite of 17 alpha-ethynylestradiol (EE2) identified in urine of women taking EE2 in oral contraceptives, and its synthetic anomer, 17 alpha-ethynylestradiol-17 beta (alpha-D-glucuronide), [EE217 beta (alpha G)], were administered intravenously to female rats in order to determine their effects on bile flow. Both agents induced an immediate, profound and dose-dependent decrease in bile flow which returned to control levels within 1-8 hr. The logarithm of the dose vs the cholestatic response curves for the two anomers were not parallel. EE217 beta (alpha G) was significantly more potent than EE217 beta (beta G) such that the doses inhibiting bile flow by 50% were 1.25 and 11 mumol/kg for the alpha-and beta-anomer respectively.

Synthesis and characterization of the anomeric pair of 17β-glucuronides of ethynylestradiol

Abstract The α- and β-anomers of the 17β- d -glucuronide conjugate of ethynylestradiol were synthesized by the SnCl4-promoted reaction between β-acetoxy GAM and the t-17β-hydroxyl group of EE2-3-acetate. The conjugates were resolved by crystallization and HPLC. Positive identification was established by u.v. spectrophotometry, i.r. and mass spectrometry and 1H- and 134C-n.m.r. The structure of the β-anomer was confirmed by X-ray crystallographic analysis. In addition, the α-anomer was refractory to hydrolysis by bovine β-glucuronidase, establishing a biochemical difference between the conjugate pair.

Synthesis of 17β-d-glucopyranosiduronic acid of 17α-ethynylestradiol

Abstract The synthesis of the 17β- d -glucuronide of 17α-ethynylestradiol was an unexpected product resulting from the use of CdCO 3 in the improved Koenigs-Knorr reaction between 17-alpha-ethynylestradiol and methyl (1α-bromo-triacetyl-glucuronate). Sephadex LH-20 was found to be effective in the purification of the synthetic product. Identification was obtained through mass spectrometry, infrared spectroscopy, ultraviolet spectroscopy, nuclear magnetic resonance spectroscopy, enzymatic and chemical analysis, and gas-liquid chromatography.

A new and improved synthesis of 19-iodocholesterol 3-acetate.

19-Iodocholesterol 3-acetate (VI) was synthesized in a single step by iodo group substitution for hydroxyl using either one of two different reagents: (1) carbodiimidonium methiodide (VIII) or (2) triphenyl-phosphine/N-iodosuccinimide (IX). The yields were as satisfactory as those obtained from the two step iodide replacement of a 19-hydroxy group via the 19-tosyloxy group. The principal intermediate, 19-hydroxy cholesterol 3-acetate (V), was derived in appreciable quantities, and relatively inexpensively, through the Pb (OCOCH3) 4 photolytic oxidation of the bromohydrin of cholesterol 3-acetate (III) to the epoxide (IV) thence Zn reduction to the 19-hydroxy compound. A specially designed 12 liter flask was of aid in accomplishing the photolysis reaction. Dry column chromatography with the supportive puncture sampling was integral to achieving the good yields and high purity of 19-iodocholesterol (VIII).

A one-step synthesis of a deuterated paclitaxel analogue : 10-deacetoxy-(10α-2H)paclitaxel

Abstract 10-Deacetoxy-(10α- 2 H)paclitaxel was prepared in one step via the samarium diiodide mediated deoxygenation of paclitaxel in the presence of D 2 O.

The identification of androstenedione and androstenedione 3-enol glucuronide in the blood of a woman with an interstitial cell ovarian tumor after 4-14C-testosterone ☆ ☆☆

After the administration of 4-14C-testosterone to a woman bearing an interstitial cell ovarian tumor, the presence of two metabolites were identified in the blood. 14C-androstenedione comprised 3% of the radioactivity in the free fraction and androstenedione 3-enol glueuronide comprised 0.5% of the radioactivity in the glucuronide fraction.

Structure-function relationship of 3-phosphoglycerate analogues with platelet aggregation and thromboxane A2 formation.

We have studied the effects of 2,3-diphosphoglycerate (2,3-DPG), 3-phosphoglycerate (3-PG), 3-phosphoglyceraldehyde (3-PGA), 2-phosphoglycerate (2-PG) and beta-glycerol phosphate (beta-GP) on platelet aggregation and on thromboxane B2 (TXB2) formation. The results show that 2,3-DPG, 3-PG, and 3-PGA inhibited platelet aggregation and TXB2 formation induced by norepinephrine, ADP, epinephrine, and collagen; but they also induced platelet aggregation and TXB2 formation in the presence of subthreshold concentrations of Na arachidonate. 2-PG and beta-GP were inactive. The results also show that there is a structure-function relationship between 2,3-DPG, 3-PG, and 3-PGA with platelet aggregation phenomena and prostaglandin synthesis.

The combined effects of 2,3-DPG and Na-arachidonate on platelet aggregation and on TXA2 formation

We have investigated the effects of 2,3-DPG on platelet aggregation in the presence of suboptimal concentrations of Na-Arachidonate by using the two cuvette transfer experiments of Hamberg, Svensson and Samuelsson (3). The results show that 2,3-DPG enhanced or induced platelet aggregation in the presence of suboptimal concentrations of Na-Arachidonate. Imidazole, a TXA2 synthetase inhibitor, and Lasix, when added inhibited 2,3-DPG effects on platelet aggregation, suggesting that 2,3-DPG may act either on cyclooxygenase or on TXA2 synthetase of prostaglandin synthesis. A specific RIA assay showed that 2,3-DPG when added to suboptimal concentrations of Na-Arachidonate enhanced the formation of TXB2, a stable metabolite of TXA2. We have concluded that during intravascular hemolysis 2,3-DPG release may be a key component in preventing and/or inducing thrombosis.

Measurement of blood plasma cortisol by p-hydrazinobenzene sulfonic acidH3PO4 reagent; a modified porter-silber reagent of increased sensitivity

Abstract A reagent combination, 275 mg % p -hydrazinobenzenesulfonic acid in 19.5 n H 3 PO 4 , is presented that has an increased sensitivity for the measurement of plasma 17α,21-dihydroxy-20-keto steroids. A plasma sample of 2 ml is sufficient for measurement of the cortisol concentration.