Mortimer B. Lipsett

Pituitary and Gonadal Hormones in Women during Spontaneous and Induced Ovulatory Cycles

A series of spontaneous cycles were selected on the basis of 2 presumptive indicators for ovulation: 1) biphasic basal body temperature curves and 2) a postovulatory interval of 13 days or more measured from the day of the LH peak until the onset of the following menses. In these 18-35 year old women daily determinations of plasma concentrations of FSH LH 17-hydroxyprogesterone and progesterone were measured. Cycles induced with clomiphene citrate were similarly studied. LH pattern is characterized by 2 features a peak more than twice the mean of values observed prior to or after it and a tendency for mean LH concentrations to rise during the follicular phase before the peak and to decline during the luteal phase after the peak. During the follicular phase mean plasma FSH values progressively increase followed by a decline during the second half of the follicular phase the ovulatory nadir. This is followed by an abrupt midcycle peak which usually occurs on the day of the LH peak after which mean values of FSH decline. Plasma progesterone rose slowly after the day of the LH peak and peaked 5-8 days later with the apex of the progesterone curve coinciding with the FSH luteal phase nadir. This was also correlated with increasing body temperatures. Mean plasma 17-hydroxyprogesterone reached a peak concentration coincident with the midcycle LH peak and remained elevated along with progesterone while FSH and LH declined. The pattern of hormonal changes induced by clomiphene citrate varied from those spontaneous cycles studied. An hypotheses concerning interactions of hypophysis and ovary is presented. It is concluded that the data demonstrate conclusively that the added sensitivity and practicality dimensions that radioimmunoassays and protein-binding assays afford make it possible to accurately and precisely evaluate perturbation effects on the hypothalamic-hypophyseal-ovarian axis when hormonal secretions by its components are studied simultaneously.

Testosterone and Androstenedione Blood Production Rates in Normal Women and Women with Idiopathic Hirsutism or Polycystic Ovaries

The average plasma testosterone concentration of women with either hirsutism or polycystic ovaries and hirsutism was higher (p < 0.01) than that of normal women although the ranges overlapped. Testosterone blood production rates averaged 830 +/- 120 SE and 1,180 +/- 310 SE mug per day in the two groups of hirsute women and 230 +/- 33 SE mug per day in normal women. The ranges did not overlap. The testosterone metabolic clearance rates of hirsute women (1,090 +/- 140 SE L per day) and of men (1,240 +/- 136 SE L per day) were significantly higher than those of normal women (590 +/- 44 SE L per day). These differences persisted when the metabolic clearance rates were corrected for surface area. We suggest that testosterone metabolic clearance rates vary directly with some function of testosterone production. The mean plasma androstenedione levels (2.8 +/- 0.35 SE and 2.8 +/- 0.30 SE mug per L) and production rates (6,060 +/- 450 SE and 7,360 +/- 345 SE mug per day) of the women with hirsutism or polycystic ovaries, respectively, were significantly higher than those of normal women (1.5 +/- 0.22 SE mug per L; 3,300 +/- 830 SE mug per day). The androstenedione metabolic clearance rates were the same in each group. Plasma androstenedione was the precursor of 49% of plasma testosterone in normal women and of 26% of plasma testosterone in hirsute women. Thus, 74% of the plasma testosterone in these subjects must have been either secreted or derived from a precursor that did not enter the plasma androstenedione pool.

Five years' experience with the chemotherapy of metastatic choriocarcinoma and related trophoblastic tumors in women

Abstract In 63 women with metastatic trophoblastic disease, intensive chemotherapy with the folic acid antagonist amethopterin supplemented in some by vincaleukoblastine, an oncolytic plant alkaloid, has led to complete remission in 30 patients who have been free of hormonal, radiological, or physical evidence of residual disease for from 6 months to 5 years. Seven patients now in incomplete remission continue on treatment. In addition, of the 26 patients who have died, 22 had obtained substantial but incomplete remission. Such remissions were characterized by marked suppression of tumor, in many instances leaving a persistently elevated hormone titer as the only evidence of persistent disease. Such incomplete remissions have lasted from 1 month to more than 43 months. The hazards of toxicity attendant upon this intensive form of chemotherapy may be largely obviated by proper case selection, by less intensive therapy in patients with liver or renal impairment, and by adequate supportive medical and nursing care, thus rendering the risk involved clinically acceptable. The highly variable clinical course of choriocarcinoma and related trophoblastic disease, with its indeterminate frequency of spontaneous regression, renders an exact appraisal of therapeutic accomplishment very difficult. However, the present data clearly establish the substantial therapeutic value of intensive chemotherapy in women with metastatic tumors of trophoblastic origin.

Estrone Sulfate: Production Rate and Metabolism in Man

Since estrone sulfate (E(1)S) is present at high concentration in plasma, we have examined the parameters of the plasma estrone, estradiol, E(1)S system. The metabolic clearance rate of E(1)S was 157 liter/day (range 70-292) in men and women. Estimated plasma production rates of E(1)S were (mugrams per day): men, 77; women, early follicular phase, 95; women, early luteal phase, 182. The conversion of plasma estrone and estradiol to E(1)S was measured and from these data and the metabolic clearance rates of the estrogens, the transfer factors were rho(E) (1) (E) (1) (S) = 0.54 and rho(E) (2) (E) (1) (S) = 0.65. Using average production rates, all plasma E(1)S could be shown to be derived from plasma estrone and estradiol. The conversion of plasma E(1)S to plasma estrone and estradiol was studied. The calculated transfer factors were: rho(E) (1) (SE) (1) = 0.21, rho(E) (1) (SE) (2) = 0.014. Essentially, similar data were obtained when E(1)S was given by mouth to two subjects. WE CONCLUDE: (a) E(1)S is a major circulating plasma estrogen and has a long plasma half-life; (b) the large contributions of estrone and estradiol to plasma E(1)S are more than sufficient to account for all the circulating plasma E(1)S.

Clinical and pathophysiologic aspects of adrenocortical carcinoma

Abstract Adrenal cortical carcinoma is a highly malignant cancer that is usually diagnosed late in its course. The presenting complaints may be those due to the mass or those resulting from the secretion of large amounts of physiologically active steroids. Some of the distinctive features of adrenal cortical carcinoma are its large size at the time of diagnosis, the generally large amounts of steroids excreted in the urine when the tumor is functional, the increased excretion of dehydroepiandrosterone (DHEA) when 17-ketosteroid (17-KS) excretion is high, and the increased excretion of tetrahydro substance S (THS) when 17-hydroxycorticosteroid (17-OHCS) excretion is increased. The rate of surgical cure is low. Following an attempt at resection of the carcinoma it is suggested that the excretion of steroids in the urine be examined at frequent intervals so that metastasis may be detected early and treatment initiated.

Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease.

We have studied a man suspected of having primary cortisol resistance on the basis of high 24-h mean plasma cortisol levels (27.4 micrograms/dl) and no stigmata of Cushings syndrome. His son had slightly elevated 24-h mean plasma cortisol levels (9.9 micrograms/dl; normal 7.52 micrograms/dl). Both had high plasma protein unbound cortisol and increased urinary free cortisol. Plasma ACTH concentration was high, and both were resistant to adrenal suppression by dexamethasone. The father appeared to have mineralocorticoid excess resulting in hypertension, hypokalemia, and metabolic alkalosis. This was found to be due to markedly elevated plasma levels of deoxycorticosterone and corticosterone. The son, who was normotensive, had mildly increased plasma corticosterone and normal deoxycorticosterone levels. To study the apparent end-organ resistance to cortisol, we examined the glucocorticoid receptor in the white cells and fibroblasts of these patients. In both tissues, using both whole cell and cytosol assays, the glucocorticoid receptor was found to have reduced affinity for dexamethasone. In the cytoxol assays, a reduced receptor number was found as well. We conclude that cortisol resistance is a rare familial syndrome owing to an abnormal glucocorticoid receptor with a decreased affinity for cortisol.

CHEMOTHERAPY OF ADRENOCORTICAL CANCER WITH o,p′DDD

Excerpt Our approach to the chemotherapy of adrenocortical carcinoma is based upon the original observations of Nelson and Woodard.1They observed that the oral administration to dogs of the insecti...

The measurement of estrone sulfate in plasma

Abstract Estrone sulfate in plasma has been measured by extraction of the conjugate, solvolysis and radioimmunoassay of estrone. Plasma concentrations are: men, 330 pg/ml; women, follicular phase, 467 pg/ml; women, luteal phase, 891 pg/ml.

Studies of the pituitary-Leydig cell axis in young men with hypogonadotropic hypogonadism and hyposmia: comparison with normal men, prepuberal boys, and hypopituitary patients

Pituitary and gonadal function was studied in seven chromatin-negative men, ages 15-27 yr, with retarded sexual and somatic development, skeletal anomalies, and hyposmia. These hyposmic patients were compared with normal men, prepuberal boys and hypogonadal patients with hypopituitarism. The urinary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels of hyposmic subjects were the same as those of normal boys and hypopituitary patients but significantly lower than those of normal men. Clomiphene citrate did not cause an increase in plasma FSH and LH levels in either hypogonadal group as it does in normal men. In contrast to hypopituitary patients, thyroid and adrenocortical function and release of growth hormone in the hyposmic subjects were normal. The plasma testosterone levels were equally low in prepuberal, hypopituitary, and hyposmic patients but were increased to a greater extent by human chorionic gonadotropin (HCG) treatment in prepuberal and hypopituitary subjects than in the hyposmic patients. Prolonged treatment with HCG has failed to return plasma testosterone levels to normal in two hyposmic patients. These observations suggest that there are defects of both pituitary and Leydig cell function in men with the syndrome of hypogonadism, skeletal anomalies, and hyposmia. They have impaired secretion of FSH and LH and a Leydig cell insensitivity to gonadotropin.

Humoral Syndromes Associated with Nonendocrine Tumors

Excerpt Dr. Mortimer B. Lipsett: During the past 10 years, the oncologist and endocrinologist have become increasingly aware of the occurrence of several endocrine syndromes in association with neo...