Robert B. Greenblatt

Clinical studies with an antigonadotropin-Danazol.

Laboratory and clinical evaluation of Danazol a synthetic (23-isoxozol) derivative of 17-alpha-ethinyl-testosterone is discussed. Danazol was administered to 8 volunteers for control studies and to 62 patients for a variety of gynecologic and endocrine disorders in oral doses of 800 mg/day in adults and 200-400 mg/day in children for a period of 21 to 240 days. Oral administration of Danazol to humans displayed a profound inhibitory effect on gonadal function. In females estrogenic activity was abolished or considerably reduced and there was no evidence of ovulation. The midcycle ovulatory surge of LH and FSH failed to occur during treatment. In 2 patients with elevated total urinary gonadotropins the titers were lowered while on medication. The effects of Danazol were reversible and confined to treatment period. In addition to antigonadotropic properties Danazol demonstrated some androgenicity especially in patients already displaying such tendencies. Long term weight gain was noted in about 40 percent of cases and considered an expression of anabolic action. No estrogenic progestational or antiprogestational effects were observed. Clinical finding are essentially in agreement with results of animal experiments. A discrepency is noted as to progestational-like effect. In animals pre-treated with estrogen injections of Danazol produced a progestational-like change in the endometrium. No such effect was observed in humans. The difference may be due to the different route of administration. Danazol was administered for therapeutic purposes to patients in whom amenorrhea suppression of gonadal steroids or inhibition of pituitary gonadotropins was expected to be beneficial. The clinical application of Danazol appears to be of particular advantage in cases of precocious puberty endometriosis virginal breast hypertrophy and chronic cystic mastitis.

Role of estrogens and progesterone in the etiology and prevention of endometrial cancer: Review

Our present knowledge of the role of sex steroids in the development as well as the prevention of endometrial cancer is reviewed. Factors which increase the exposure of the uterus to unopposed estrogens, either exogenous or endogenous, are associated with increased risk of endometrial adenocarcinoma. However, there is increasing evidence that progestogens can reverse endometrial hyperplasia and protect against the development of endometrial cancer. The mechanisms to explain the antiestrogenic effects of progestogens include changes in enzyme activity and steroid receptors in endometrial tissue. Postmenopausal women treated with combined estrogen and progestogen have the lowest incidence of endometrial carcinoma. Oral contraceptives containing both estrogen and progestogen in each tablet are protective against adenocarcinoma of the endometrium, while the sequential oral contraceptive pills afforded less protection. The risks and benefits of these hormone therapies are discussed in relation to the etiology and prevention of endometrial cancer.

Danazol—a Synthetic Steroid Derivative with Interesting Physiologic Properties

The antigonadotropic antiandrogenic and androgenic estrogenic antiestrogenic progestational and antiprogestational activities of Danazol were investigated in rats mice and rabbits. Injection of Danazol to hemicastrated or intact male or female rats led to a suppression of gonadal growth development and steroidogenesis which could be reversed by the administration of exogenous gonadotropins. There was no evidence of competitive inhibition of the exogenous gonadotropins. The above effects were significant at a dosage of 4 mg/kg. In immature rabbits dosages of 10 and 40 mg/kg led to secretory-like changes of the proliferative endometrium. There were no definite progestational or antiprogestational effects observed. The compound demonstrated a weak mytrophic effect as judged by the weight of musculus levator ani.

The spectrum of gonadal dysgenesis: A clinical, cytogenetic, and pathologic study

Thirty-one patients with anatomical verification of the diagnosis of gonadal dysgenesis have been assessed as to possible correlations between clinical, cytogenetic, and histologic findings. No significant differences in histopathology were detected. Characteristically, histologic sections exhibited fibrous stroma and. mesonephric remnants with sporadic occurrence of Leydig or hilar cells. On the other hand, clinical and cytogenetic findings were quite variable. The clinical spectrum included patients of short, normal, and tall stature, some with and some without associated somatic anomalies. Among the 31 patients, cytogenetic studies revealed eleven different sex chromosome patterns including normal XX complements. There appeared to be some correlation between the amount of genetic privation and the incidence of somatic anomalies. Analysis of all data has led to the conclusion that most cases of gonadal dysgenesis may be diagnosed on the basis of clinical and cytogenetic findings alone. However, of special interest are a smaU minority of patients who require gonadal visualization for definitive diagnosis and accurate prognosis.

The use of an impeded androgen—danazol—in the management of benign breast disorders

Danazol, an impeded androgen with moderate antigonadotropin properties, was administered to 58 patients with a variety of benign breast disorders. The disturbances were present from 3 months to 20 years; the ages ranged from 21 to 50 years. The dose varied from 100 to 400 mg. per day for 74 to 310 days, depending upon the severity of the disorder. Most of the patients had favorable responses: 44 (75.8 per cent) experienced complete relief of subjective discomfort with disappearance of clinical signs; 17 (65.3 per cent) of the 26 patients followed from 11 to 32 months after discontinued therapy, remained symptom-free, while the others experienced moderate to complete recurrence. Fifty per cent of the women did not menstrate while on medication. Side effects were few and transient.

Ovarian, adrenal, and peripheral testosterone levels in the polycystic ovary syndrome

Abstract Twenty patients with clinically diagnosed Stein-Leventhal syndrome have been tested with the use of selective adrenal and ovarian venous catheterization. Nine of these patients were found to have combined adrenal and ovarian androgen hypersecretion, 8 were shown to have excess androgen production of adrenal origin, and 3 were demonstrated to have elevated testosterone levels because of peripheral conversion. No patient in this group demonstrated excess androgens of ovarian origin alone. The etiology of androgen hypersecretion seems to have been correctly suggested by this method of evaluation in patients in whom adequate follow-up was obtained. There appears to be no morbidity with this test. Testosterone assays are available from commercial sources and, if radiologic support is available, this technique can be used by gynecologists in general. Treatment to restore fertility, based on the results of this test, needs further study and is being evaluated.

Indications for hormonal pellets in the therapy of endocrine and gynecic disorders

Abstract The implantation of hormonal pellets has proved of value in the management of a great variety of endocrine and gynecic disorders. Pellet implantation is indicated in those conditions where prolonged hormonal therapy appears necessary. With the use of the Kearns Pellet Injector, pellet implantation is a simple office procedure. Some of the indications and contraindications for pellet implantation are listed. A number of typical case reports are cited in which pellet implantation was of definite benefit to the patient. It appears that the pellet method of hormone administration has more nearly approached the endogenous rate of hormonal secretion. Furthermore, its use has made possible a clearer understanding of the physiologic properties of certain steroids. Testosterone and desoxycorticosterone acetate pellets are now commercially available, and it is hoped that pellets of estradiol and progesterone will soon be made available for general use.

Estrogen-Androgen Levels in Aging Men and Women: Therapeutic Considerations*

ABSTRACT: The influence of aging on serum levels of gonadotropins (FSH and LH), testosterone and estradiol was studied in the following groups: 4 normal men (ages 30 to 50), 38 men with symptoms of the male climacteric (ages 51 to 84), 25 men with relative impotence (ages 31 to 50), 10 normal women (ages 24 to 31), and 6 menopausal women (ages 58 to 76). FSH and LH levels began to rise in men in their 40s, and the increase became more conspicuous in the later age decades. The degree of elevation was nowhere comparable to that observed in the aging women. In the male, the serum testosterone levels showed a progressive decrease from the fifth age decade onward, whereas in the female there was an increase after the menopause. Estradiol levels showed no significant change in the aged male, but they were somewhat higher than in the aged female. Exceptions to the low‐testosterone and low‐gonadotropin relationship were observed in individual cases and might be explained by relatively high estradiol values. Proper replacement therapy by means of estrogens for the postmenopausal female and androgens for the aging male is often of great benefit, physically and emotionally.

Meckel's diverticulum

Abstract The lesions of this common anomaly are so manifold that it should be entertained in every puzzling abdominal diagnosis. Because of its varied and bizarre morbid states, no one definite syndrome can be ascribed to it. The recent numerous articles on the subject have given this frequent and dangerous anomaly a deserved place, for more and more think of it in differential diagnoses. In reviewing the literature, one is impressed with the frequency of secondary laparotomies following appendectomy or salpingectomy, etc., for the removal of a troublesome Meckels diverticulum. Many unnecessary operations and failure of an appendectomy to relieve vague abdominal pains have been now explained by the fact that a Meckels diverticulum was overlooked. Surgeons have not searched for this frequent anomaly, estimated as occurring in 1.5 to 3 per cent of all persons. The argument “to leave well enough alone” is to be condemned, for the diverticulum resembles and yet is so unlike the appendix, that when both are present, the chance of morbid pathology in the diverticulum because of its position, structure and development, is tenfold that of the appendix vermicularis. The appendix, however, is removed at laparotomy in the majority of cases; a second operation, therefore, is deprecated. The diagnosis could be made more frequently, for quite often the “sign on the door” is overlooked. The presence of an umbilical adenoma, a history of fecal discharge from the umbilicus or of cryptic rectal hemorrhages should be pointers. The admonition of Cullen remains unheeded. In his book, “The Umbilicus and its Diseases,” the following paragraph appears in large print: In every case of umbilical polyp it is the duty of the family physician or surgeon to explain carefully to the parents the possible coexistence of an intra-abdominal portion of the omphalomesenteric duct, which may be adherent to the umbilicus and later give rise to intestinal obstruction. Their parents should be instructed to watch such children carefully, and if later in life the slightest sign of intestinal obstruction develops an abdominal operation should be immediately undertaken, the surgeon making an incision encircling the umbilicus and looking immediately for an adherent Meckels diverticulum. If this review and analysis of cases does nothing more than impress the reader with the necessity of looking for a Meckels diverticulum, when feasible, in all laparotomies, it has served its purpose. It is hoped that with the gradual correlation of symptoms manifested by this group complex and the spreading of its knowledge, the diagnosis will be made oftener in its earlier phases and surgical treatment will be more efficacious.

The metabolic clearance rate and urinary excretion of oral contraceptive drugs

The plasma metabolic clearance rate (MCR) and the urinary excretion of norethindrone were measured in 8 volunteer women, who took Norlutin (2.5 mg norethindrone per day for 20 days per month) for 6 to 7 months. MCR increased significantly (p.05) after 6 months of norethindrone medication. Urinary excretion of norethindrone and its metabolites did not change significantly after the 6 month course. Variability in the MCR measurements among the subjects could not be accounted for by size differences or different times of the menstrual cycle. Total plasma radioactivity (from tritiated norethindrone) fell much more slowly than plasma norethindrone levels; this is probably due to conjugated metabolites of norethindrone.