Udall J. Salmon

The use of estrogens in the treatment of dysuria and incontinence in postmenopausal women

Abstract The study reported here stems from the observation that a number of women with disorders of micturition, consisting of urinary frequency, urgency, and incontinence, experienced relief of these symptoms while being treated with estrogens for the usual menopausal complaints. In order to determine the relationship of the estrogen therapy to the amelioration of the urinary symptoms, a group of postmenopausal patients with urgency, dysuria, and stress incontinence were selected for study and treatment.

Effect of Testosterone Propionate upon Gonadotropic Hormone Excretion and Vaginal Smears of Human Female Castrate

It has been previously shown that the excessive gonadotropic hormone excretion which occurs after castration in females can be controlled by the administration of adequate amounts of estrogenic substance. 1 Butenandt and Kudzus 2 have shown that testosterone, if given in sufficiently high doses, causes premature opening of the vagina in infantile rats. The present investigation was undertaken to determine (a) whether the gonadotropic hormone can be made to disappear from the urine of a female castrate by the exhibition of male hormone and (b) whether at the same time an estrogenic effect can be demonstrated in the vaginal smears of the castrated patient. The patient studied was 46 years of age and had had an hysterectomy and bilateral salpingo-oophorectomy 6 years before the present investigation. During a preliminary study of 20 days (started February 13, 1937) the urine was found to be constantly positive for G. H. (the excretion varying from 13 to 27 R.U. per day) and the vaginal smears were uniformly negative. (Fig. 1.) The acetone precipitation method was used for G.H. determination in the urine. 3 The vaginal smears were prepared and graded according to the technic and classification previously reported, 4 reactions I and II representing “negative” smears and III and IV “positive” smears. The patient was given 815 mg. testosterone propionatef in solution in sesame oil in divided doses intramuscularly over a period of 27 days. Individual doses varied from 10 to 50 mg. G.H. determinations and vaginal smears were performed throughout the period of observation of 92 days. The results are represented in Graph 1. The G.H. factors began to disappear from the urine after 465 mg. of testosterone had been administered. For a period of 18 days the urine remained negative for G.H. Following this, G.H. reappeared in the urine in increasing concentration. Coincident with the disappearance of G.H. from the urine large epithelial cells which exhibited various degrees of cornification appeared in the vaginal smears displacing completely the “compact cells” (Papanicolaou) and the leucocytes, thus representing a full estrogenic effect. (Fig. 2.) The maximum effect on the smear lasted for 21 days, following which a gradual return to the pre-treatment status occurred. The regression of the smear ran parallel with the reappearance of G.H. in the urine. It is interesting to note that the patient began to experience relief of her symptoms (flashes, headaches, etc.) after 400 mg. of testosterone propionate had been administered. The amelioration of symptoms reached its maximum at the time when the smear exhibited a full estrogenic effect and the urine was negative for G.H. Symptoms recurred rapidly with the reappearance of G.H. in the urine and the regression of the smear to its pre-treatment status. Identical effects (as regards both G.H. excretion and vaginal smears) had been produced in the same patient 24 months previously with 16,000 R.U. of estradiol benzoate. It would appear from this study that testosterone propionate when given in adequate dosage can inhibit the gonadotropic hyper-activity of the hypophysis in a female castrate and also produce a full estrogenic effect on the vaginal mucus membrane of a human castrate—thus paralleling two phases of biologic activity of the estrogenic substances.

Excretion of Pregnandiol in Women with Virilism

Butler and Marrian 1 in reporting the isolation of a steroid compound pregnane-3-17-20-triol, from the urine of 2 women with virilism caused by “enlarged adrenals,” also noted the presence of “appreciable amounts of pregnandiol.” Venning, Weil and Browne 2 later reported the finding of considerable amounts of sodium pregnandiol glucuronidate (12 mg to 30 mg per day) in 2 cases of virilism, one of which was subsequently found to have an adrenal cortex carcinoma and, the other, adrenal cortex hyperplasia. During the past 2 years, we have been performing pregnandiol excretion studies in women with the arrhenomimetic (virilism) syndrome. In the present communication, we wish to report the results of these studies. Methods and Materials. A total of 7 cases was studied. These consisted of 2 cases proven by operation to be adrenal cortex carcinomas and 5 cases of amenorrhea and hypertrichosis of undetermined etiology. Sodium pregnandiol glucuronidate determinations 3 were performed on single 24-, 48-, or 72-hour specimens, for periods varying from 6 to 32 days. Results. Pregnandiol Excretion in Patients with Adrenal Cortex Carcinoma. In the 2 patients in whom adrenal cortex carcinomas were found, the pregnandiol excretion varied in one from 9 to 20 mg per day and, in the other, from 12 to 18 mg per day. In one patient (I.E.), in whom it was possible to obtain post-operative urines, these were found to contain no detectable amount of pregnandiol after removal of the tumor. Pregnandiol Excretion in Patients with Arrhenomimetic Syndrome (without adrenal cortex carcinoma). In the 5 cases in this group, X-rays of the adrenals after intravenous pyelogram and peri-renal insufflation failed to reveal any evidence of adrenal tumor or enlargement. Two of these (E.W. and T.S.) were explored surgically without revealing any evidence of adrenal neoplasm.

Are Estrogens Carcinogenic in the Human Female

A case report of a 52-year-old patient gravida 3 and para 2 in whom menstruation had ceased 2 years previously is presented. Small uterine fibroids were present. She received 40000 RU of alpha-estradiol-benzoate in less than 2 months. Several months later spontaneous uterine bleeding occurred. A small cervical polyp was removed. The endometrium at that time showed areas of proliferation with other areas of hyperplasia. In a period of about a month she received 234000 RU of alpha-estradiol-benzoate and 65 mg of progesterone im. Before the progesterone was given an endometrial biopsy revealed advanced proliferation with areas of cystic hyperplasia. After progesterone therapy the endometrium showed proliferation and secretory phenomena. 6 months later evidence of estrogen deficiency was present and a pellet of 25 mg of crystalline alpha-estradiol was implanted sc. Her symptoms subsided. 7 months later menopausal symptoms recurred. The implantation site was excised after an additiona l 2 months. Endometrial and vaginal biopsies then showed endometrial regression and evidence of estrogen deficiency in the vaginal biopsy. At this time 29 mg of crystals of alpha-estradiol-benzoate were implanted. After 6 weeks uterine bleeding occurred and intermittent spotting persisted for 6 weeks. Then endometrial biopsy showed advanced proliferation and dilated glands. A later biopsy showed a variable pattern with some atypical glands. 1 month later a diagnostic curettage under anesthesia was done. A diagnosis of adenocarcinoma was made on the tissue removed. A hysterectomy was then done. The uterus contained 2 small myomas and an endometrial polyp but no carcinoma metaplasia or cellular atypica was found. A benign endometrial condition was believed to have been present although consulting pathologists who reviewed the slides were divided as to whether an early carcinoma had been present.

The treatment of dysmenorrhea with testosterone propionate

The subject of dysmenorrhea has engaged the attention of numerous investigators and an extensive literature has accumulated on the subject. The etiology of this distressing condition, however, is still obscure and its treatment still unsatisfactory. Reviews of the various hormonal theories of the cause of dysmenorrhea have recently been published by several authors.1–4 Briefly, there are three current theories as regards the etiology of dysmenorrhea: (a) Deficiency in progesterone, permitting of the unopposed action of estrogenic hormone upon the uterine muscle; (b) excessive estrogen production resulting in hypermotility of the uterine musculature; and (c) excessive progesterone activity.5 None of these theories is, however, adequately supported by controlled experimental studies. The present communication deals with the treatment of dysmenorrhea with male hormone (testosterone propionate). The rationale for this form of therapy is based on the observation that testosterone counteracts certain of the physiologic effects of the estrogens in animals and human beings.Abstract The subject of dysmenorrhea has engaged the attention of numerous investigators and an extensive literature has accumulated on the subject. The etiology of this distressing condition, however, is still obscure and its treatment still unsatisfactory. Reviews of the various hormonal theories of the cause of dysmenorrhea have recently been published by several authors. 1–4 Briefly, there are three current theories as regards the etiology of dysmenorrhea: (a) Deficiency in progesterone, permitting of the unopposed action of estrogenic hormone upon the uterine muscle; (b) excessive estrogen production resulting in hypermotility of the uterine musculature; and (c) excessive progesterone activity. 5 None of these theories is, however, adequately supported by controlled experimental studies. The present communication deals with the treatment of dysmenorrhea with male hormone (testosterone propionate). The rationale for this form of therapy is based on the observation that testosterone counteracts certain of the physiologic effects of the estrogens in animals and human beings.

Estrogenic Substances in the Blood and Urine After Castration and the Menopause

We noted that the blood cycle persists after hysterectomy. 1 We reported the recovery of estrogenic substances from the blood 2 and urine 3 years after the onset of the physiological menopause. The present report deals mainly with the finding of estrogenic factor in the urine of human castrates. The report is based on the study of 12 female surgical castrates, 5 physiological menopause patients and 3 X-ray castrates. 1. All of the 12 surgical castrates excreted estrogenic factor in the urine. The amount varied between 15-200 M.U.L. In 2 cases, aged 23 and 44 years, studied over a months period, a total of 255 M.U. and 720 M.U. respectively, were excreted. The average normal excretion of a menstruating woman in the same period equals 1500 M.U. 3 Blood studies of these 2 cases failed to show estrogenic factor. 2. No correlation could be demonstrated between the relative amount of estrogenic and prepituitary gonadotropic factor of the urine. Seven patients were studied. With high readings of both luteinizing and follicle stimulating factor as little as 15 M.U.L. of estrogenic factor and as much as 200 M.U.L. were encountered. 3. No difference was noted between castration (2 cases) and castration with removal of the uterus (10 cases). 4. The subjective symptoms (flushes, arthritis) showed no correspondence with the amount of estrogenic factor excreted—6 “mild” cases with from 40 to 200 M.U.L.; 6 “severe” cases with 15 to 200 M.U.L.

Hormonal Factors Affecting Vaginal Smears in Castrates and After the Menopause

Papanicolaou and Shorr 1 have recently described the cytological characteristics of the vaginal smear found in castrates and in women after the menopause. As described by these authors, the smears contain “many leucocytes and a predominance of either non-cornified squamous cells with larger nuclei or of compact cells derived from the deeper layers of the vaginal epithelium, with large well-preserved nuclei.” 1 By the administration of estrogenic substance hypodermically these investigators were able, in 14 out of 15 cases, to demonstrate a change in these smears so that they resembled the “follicular (copulative) phase in the normal female.” 1 This phase is characterized by “leukopenia and epithelial cells of the squamous type, largely cornified with small pyknotic nuclei.” 2 These effects on the smears disappeared several days after cessation of the treatment. We have recently reported the finding of large quantities of luteinizing factor as well as follicle stimulating factor in both the urine and blood of castrates and natural menopause cases 3 and found that both these factors disappear from the urine and blood following the administration of concentrated estrogenic substance (Progynon-B). 4 The present investigation was undertaken to determine whether any relationship existed between the type of vaginal smear, the gonadotropic hormone excretion and the symptoms in post-menopause cases and in surgical and X-ray castrates. A group of 45 cases was studied, consisting of 24 surgical castrates, 11 X-ray castrates and 10 natural menopause.

Effect of Administration of Estrogenic Factor upon Hypophyseal Hyperactivity in the Menopause

Summary In 14 menopause cases in which a hyperexcretion of gonadotropic factor was observed, injection of 4,000 to 22,000 R.U. of estrogenic factor was followed by a rapid decrease of gonadotropic factor in the blood and urine. The disappearance of the prepituitary hormone persisted for from 28 to 70 days but was regularly followed by a return to the condition noted before treatment. The amelioration of subjective symptoms roughly paralleled the decrease of the gonadotropic factor in the urine. From these studies it appears that the hypophyseal hyperactivity which follows castration or appears in the spontaneous menopause (Zondek, 4 Fluhman 5 ) can be temporarily ameliorated by the administration of estrogenic factor in high dosage. Graph of a typical case is appended.

Gonadotropic Effect of Androgens upon the Immature Rat Ovary

Butenandt and Kudzus 1 have reported that androgenic substances administered to immature female rats cause premature opening of the vagina. The present study was undertaken to determine whether the androgens produce this effect directly upon the genital tract or indirectly through the ovary. Eighteen rats (comprising 5 litters), varying in age from 27 to 30 days, were used in this study. Twelve were given a single injection of androgen in sesame oil; 6 controls were given an equal quantity of pure sesame oil. Seven of the animals were injected with testosterone propionate and 5 with androstenediol,† the dosage varying from 1 to 5 mg. The time of the opening of the vagina was noted in each case. Laparotomies were performed and one ovary removed at intervals varying from 60 to 96 hours after the administration of the androgen. The animals were sacrificed at periods varying from 96 to 228 hours after the injection and the remaining ovary was then removed. At corresponding intervals, the ovaries were removed from the control animals. The ovaries were examined microscopically in serial sections. Opening of the vagina occurred in all androgen-injected animals within 72 hours after the injection. Follicle stimulation was noted as early as 60 and 72 hours after the injection. Corpora lutea were found as early as 96 hours and as late as 192 hours after androgen administration. The ovaries of all the 12 injected animals exhibited some gonadotropic effect, either follicle stimulation, luteinization or both. The uteri in all these animals were markedly enlarged. In the 6 control rats, the vaginas remained closed and the ovaries were negative. Eighteen rats (comprising 5 litters), varying in age from 27 to 30 days, were used in this study. Twelve were given a single injection of androgen in sesame oil; 6 controls were given an equal quantity of pure sesame oil.

Effect of Testosterone Propionate on Glycogen Content of Human Vaginal Smears

Summary A method of demonstrating simultaneously the presence of glycogen and the morphologic characteristics of the desquamated cellular elements of the vaginal mucosa is presented. The glycogen in the desquamated vaginal epithelial cells of normally menstruating women can be made to disappear by administering adequate amounts of testosterone propionate. The disappearance of the glycogen is apparently dependent upon the production of atrophic changes in the vaginal mucosa since the first effect of the testosterone propionate is the disappearance of the squamous epithelial cells and their replacement by cells from the deeper layers of the mucous membrane. Coincident with this change in the size of the cells, the glycogen begins to decrease steadily and finally vanishes completely. Restoration of the glycogen in the smears parallels closely the reappearance of the normal vaginal epithelium. The question arises as to the mechanism of this regression in the smear and the disappearance of the glycogen. There is experimental evidence indicating that androgens negate the biologic effect of estrogens. 1-3 It is, therefore, conceivable that the testosterone propionate in the cases reported here inactivated the estrogen formed in the individual and, as a result, atrophy of the vaginal mucosa occurred with loss of cornification and consequent disappearance of glycogen. It seems likely, however, that the regressive changes induced in the smear are also the end results of inhibition of the gonadotropic hormone formation of the hypophysis resulting in suppression of the follicular ovarian cycle. That the testosterone propionate probably inhibits the hypophysis is suggested by the following observations: (a) the excessive gonadotropic hormone excretion in a human female castrate can be suppressed with testosterone propionate; 5 (b) ovulation can be similarly inhibited in monkeys; 6 (c) menstruation can be inhibited and the estrogen and progesterone effects in the endometrium of cyclical human females can be suppressed by administering adequate amounts of testosterone propionate. 7