A Study of the Metabolism of Crystalline Progesterone

Abstract

MONTREAL, CANADÃ\r N 1938 (1) a preliminary report was made on a study of the metabolism of in' II jected crystalline progesterone, which definitely established sodium pregnandiol -1L glucuronidate as an end product in the metabolism of this compound in the hu' man organism. These experiments have been elaborated and are now being reported in detail.Since this work was published Stover and Pratt (2) reported failure to demon' strate any sodium pregnandiol glucuronidate in the urine of women following injec' tions of 15 and 17.5 Rb. u. of progestin (Parke, Davis). AlsoHamblen and coworkers (3,4) reported that in their studies on progesterone utilization in patients with func' tional irregularities of uterine bleeding no evidence was encountered that crystalline progesterone was metabolized into sodium pregnandiol glucuronidate. From endome' trial studies they also conclude that progesterone is inefficiently utilized in these cases. Recently in an advance abstract (19) they state they were only able to recover a total of 3 mg. and 5 mg. of sodium pregnandiol glucuronidate from the urine of 2 patients who had received 90 mg. and 200 mg. of progesterone respectively. In a recent paper Seegar (20) reported that endometrial hyperplasia may respond to pro' gesterone and show changes resembling the physiologic response. The amount of progesterone excreted in the urine as pregnandiol when 50 mg. in 5 mg. doses is given daily, is insufficient to be recovered consistently in measurable quantities in these cases. On the other hand Buxton and Westphal (5) recovered sodium preg' nandiol glucuronidate in the urine of males following large doses of crystalline proges' terone.In the present study the excretion of sodium pregnandiol glucuronidate was fol' lowed under various conditions, and in many cases an attempt was made to correlate this excretion with simultaneous changes occurring in the endometrium. Injections of progesterone were given in the follicular and luteal phase of the menstrual cycle, during pregnancy, after hysterectomy, in cases of secondary amenorrhea with hypoplastic endometria with or without pretreatment with estrogens and in cases of metropathia hemorrhagica with hyperplasia of the endometrium. The effect of estrogens and of gonadotropic hormone upon the excretion of sodium pregnandiol glucuronidate was also investigated.The determination of sodium pregnandiol glucuronidate was made according to the method of Venning (6, 7). There are several points which should be emphasized regarding the estimation of this compound. Firstly, it is impossible to detect less than 2 mg. in a sample of urine, therefore 2 or more days must be pooled and extracted together in order not to overlook small amounts. Secondly, unless care is taken in 707 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 October 2015. at 00:22 For personal use only. No other uses without permission. . All rights reserved.

The Early History of Progesterone

“…Two years later Ethel Venning and J.S.L. Browne [17] at Montreal discovered the metabolic change of progesterone to pregnanediol by the human organism prior to its excretion in the urine -a discovery which placed a progesterone assay in the hands of the clinicians, who were by this time confirming in their patients much that had been seen in experimental animals.…”

The Excretion of Urinary Pregnanediol After the Administration of Progesterone

“…Since these two observations were made, many attempts have been under¬ taken to establish a connexion between them. At first it was thought that the endometrium was essential to the conversion of progesterone to pregnanediol [Venning & Browne, 1937;Hamblen, Powell & Cuyler, 1939]. This was disproved when it was shown that hysterectomized women and normal men could excrete pregnanediol after the administration of progesterone [Buxton & Westphal, 1939;Venning & Browne, 1940].…”

“…At first it was thought that the endometrium was essential to the conversion of progesterone to pregnanediol [Venning & Browne, 1937;Hamblen, Powell & Cuyler, 1939]. This was disproved when it was shown that hysterectomized women and normal men could excrete pregnanediol after the administration of progesterone [Buxton & Westphal, 1939;Venning & Browne, 1940]. Venning & Browne [1940] then produced evidence to show that in the presence of secretory endometrium or placenta the percentage of administered progesterone excreted as urinary pregnanediol was increased.…”

“…This was disproved when it was shown that hysterectomized women and normal men could excrete pregnanediol after the administration of progesterone [Buxton & Westphal, 1939;Venning & Browne, 1940]. Venning & Browne [1940] then produced evidence to show that in the presence of secretory endometrium or placenta the percentage of administered progesterone excreted as urinary pregnanediol was increased. They used small doses of progesterone (5-30 mg/day), and a relatively inaccurate and insensitive pregnanediol assay method [Venning, 1937].…”

“…Venning & Browne [1940] then produced evidence to show that in the presence of secretory endometrium or placenta the percentage of administered progesterone excreted as urinary pregnanediol was increased. They used small doses of progesterone (5-30 mg/day), and a relatively inaccurate and insensitive pregnanediol assay method [Venning, 1937]. It is doubtful whether much reliance, from the quantitative point of view, can be placed on results obtained by the Venning method at the low levels of urinary pregnanediol studied in this investigation.…”