Development Of Gynecomastia Research Articles

The endocrine effects of ketoconazole.

INTRODUCTION Ketoconazole l has been employed extensively in clinical practice during the last 5 years as an innovative treatment for fungal disease (1 ). This is due largely to its properties: broad-spectrum activity, easy mode of administration, widespread tissue distribution, low degree of inactivation, good patient tolerance, low toxicity profile (2). This orally-active imidazole derivative (3-5) interferes with the synthesis of ergosterol in fungi and cholesterol in mammalian cells by blocking the 14-demethylation of lanosterol (2, 6, 7). Its effects on sterol synthesis and the development of gynecomastia in some patients treated for mycosis (8-1 0), led to investigations of its ability to induce alterations in steroid hormone synthesis or action. By in vivo and in vitro studies, the drug was shown to act as a potent inhibitor of both gonadal (10) and adrenal (11) steroidogenesis. In addition to inhibition of cholesterol synthesis, several sites of action have been demonstrated. At the same time, clinical trials have established that the properties of ketoconazole as a steroid inhibitor make it a valuable tool in the management of endocrine disorders that benefit from suppression of either gonadal or adrenal hormone production. Examples include prostatic cancer and Cushing's syndrome, respectively (12). Although serum cholesterol levels are decreased in patients during chronic high dose regimens (13), there is no evidence as yet for a potential therapeutic use of ketoconazole in the management of hypercholesterolemia, since the effects of cholesterol precursor accumulation are not known (14, 15).

Ketoconazole metamorphosis. An antimicrobial becomes an endocrine drug.

The report by Shepherd et al in this issue of theArchives 1 is the latest step in an evolving story. For me, the story began in 1979, in the second year of my early studies with ketoconazole as a therapy for deep mycoses. 2 A young male patient with coccidioidomycosis, on no other medications, developed gynecomastia. It was this observation and the development of gynecomastia in a second patient receiving ketoconazole therapy the next year that led to a collaboration with Allan Pont, MD, then chief of endocrinology at Santa Clara Valley Medical Center, San Jose, Calif, to investigate whether this occurrence might be explained by a ketoconazole-induced alteration of sex hormone synthesis or action. We initially found that random testosterone determinations in several patients showed a temporal relationship with the time of their daily ketoconazole dose. We thought the best way to substantiate this relationship would be

Ketoconazole Metamorphosis

The report by Shepherd et al in this issue of theArchives¹is the latest step in an evolving story. For me, the story began in 1979, in the second year of my early studies with ketoconazole as a therapy for deep mycoses.²A young male patient with coccidioidomycosis, on no other medications, developed gynecomastia. It was this observation and the development of gynecomastia in a second patient receiving ketoconazole therapy the next year that led to a collaboration with Allan Pont, MD, then chief of endocrinology at Santa Clara Valley Medical Center, San Jose, Calif, to investigate whether this occurrence might be explained by a ketoconazole-induced alteration of sex hormone synthesis or action. We initially found that random testosterone determinations in several patients showed a temporal relationship with the time of their daily ketoconazole dose. We thought the best way to substantiate this relationship would be

Ketoconazole inhibition of testicular secretion of testosterone and displacement of steroid hormones from serum transport proteins.

In vivo perfusion of canine testes with ketoconazole inhibited the stimulation of testosterone production by human chorionic gonadotropin in a dose-dependent manner. Ketoconazole also selectively displaced steroids from serum-binding globulins. Dihydrotestosterone and estradiol binding to sex hormone-binding globulin were inhibited by ketoconazole. Cortisol binding to corticosteroid-binding globulin was unaffected. The concentrations of ketoconazole that inhibited human chorionic gonadotropin stimulation of testicular androgen production and displaced sex steroids from sex hormone-binding globulin were in the range of blood levels found in patients on higher therapeutic dosage regimens. Suppression of testicular testosterone synthesis and displacement of estrogens from sex hormone-binding globulin may decrease the androgen/estrogen ratio of the blood and contribute to the development of gynecomastia that has been reported in some ketoconazole-treated patients.

Ketoconazole Blocks Testosterone Synthesis

• Ketoconazole, a new oral drug used to treat systemic and superficial mycoses, inhibits sterol synthesis in fungi. The development of gynecomastia in two patients prompted us to investigate the effect of the drug on testosterone production. After a 200-, 400-, or 600-mg dose, volunteer male testosterone serum concentrations fell markedly, but returned toward baseline eight to 24 hours later as ketoconazole serum concentrations waned. A marked but transient drop in testosterone levels occurred in patients receiving long-term therapy, and continuous testosterone depression was noted in one. A block of synthesis was demonstrated in vitro. Ketoconazole at concentrations achievable in serum with currently used doses blocked basal and gonadotropin-stimulated testosterone production by rat Leydig cells. The diminution of testosterone synthesis could be significant as further therapeutic trials may use larger doses or more than once-daily administration. The paucity of reports of endocrinologic toxicity may relate to the "escape" from the block demonstrated in vivo. (<i>Arch Intern Med</i>1982;142:2137-2140)

Ketoconazole blocks testosterone synthesis

Ketoconazole, a new oral drug used to treat systemic and superficial mycoses, inhibits sterol synthesis in fungi. The development of gynecomastia in two patients prompted us to investigate the effect of the drug on testosterone production. After a 200-, 400-, or 600-mg dose, volunteer male testosterone serum concentrations fell markedly, but returned toward baseline eight to 24 hours later as ketoconazole serum concentrations waned. A marked but transient drop in testosterone levels occurred in patients receiving long-term therapy, and continuous testosterone depression was noted in one. A block of synthesis was demonstrated in vitro. Ketoconazole at concentrations achievable in serum with currently used doses blocked basal and gonadotropin-stimulated testosterone production by rat Leydig cells. The diminution of testosterone synthesis could be significant as further therapeutic trials may use larger doses or more than once-daily administration. The paucity of reports of endocrinologic toxicity may relate to the "escape" from the block demonstrated in vivo.

Gynecomastia After Chemotherapy for Lymphoma

Although development of gynecomastia in a patient with cancer may indicate persistence or regrowth of a tumor, we studied three patients with lymphoma in whom development of gynecomastia during or after chemotherapy did not portend a poor outcome. In all patients, serum testosterone levels were normal, serum luteinizing hormone (LH) levels were high-normal or elevated, and serum follicle-stimulating hormone (FSH) levels were clearly elevated. The serum estradiol level of one patient was elevated at the onset of gynecomastia, but it fell to normal as the gynecomastia resolved spontaneously over a three-month period during which the patient received no chemotherapy. In a second patient, gynecomastia resolved over a period of eight months while the patient continued on maintenance chemotherapy, and he remains clinically well in remission 21/2 years after onset of gynecomastia. In the third patient, gynecomastia developed while the patient was in complete remission and off of all therapy, and it remained unchanged for the duration of a 21/2-year remission without therapy. Gynecomastia after chemotherapy for lymphoma is not an ominous prognostic sign and does not necessarily indicate the need for alteration of the treatment regimen.

Gynecomastia induced in normal males by spironolactone.

The short‐term (1 week) and long‐term (10 month) effects of spironolactone have been determined in normal males. There were no adverse effects or changes in plasma testosterone, luteinizing hormone, or progesterone levels during one week of treatment with spironolactone (200 mg/day) in 6 normal men. A continuous 4‐hr sampling technique to provide an integrated plasma sample resulted in plasma hormone concentrations similar to the mean values for intermittent sampling. There was considerable intraindividual variability in the levels of each hormone. To evaluate the long‐term effects of spironolactone, 30 normal males were randomly divided into three groups: placebo, 100 mg spironolactone per day (low dose), and 100 mg spironolactone per day increased at two months to 200 mg spironolactone per day (high dose). The study was double blind and lasted 10 months. The presence of gynecomastia was determined clinically and confirmed by thermography. Two metabolic clearance studies with either 3H‐testosterone or 3H‐androstenedione were obtained (1) just before spironolactone treatment and (2) again with the same steroid either the last day of the 10‐month treatment period or with the development of gynecomastia. The concentrations of testosterone, estradiol, estriol, luteinizing hormone, follicle stimulating hormone, progesterone, and prolactin were also determined before treatment and at two‐month intervals during treatment. Eighteen individuals received spironolactone (10 in the low‐dose group and 8 in the high‐dose group); of these, 8 developed gynecomastia. There were none in the placebo group. The incidence of gynecomastia was 30% in the low‐dose group and 62% in the high‐dose group. In addition, one individual in the high‐dose group discontinued taking the drug early because of decreased libido, bringing the incidence of adverse effects in this high‐dose group to 75%. Spironolactone induced no significant changes in the metabolic clearance of androstenedione or testosterone. Plasma concentrations of the various hormones did not change as a result of either spironolactone or the development of gynecomastia. Inhibition of testosterone synthesis or alteration in its metabolic clearance by spironolactone does not appear to be the cause of spironolactone‐induced gynecomastia in man.

Endocrine studies in testicular tumor patients with and without gynecomastia: a report of 45 cases.

Prolactin (PRL), human placental lactogen (hPL), the beta-subunit of human chorionic gonadotropin (betahCG), testosterone (T), estrone (E1), and estradiol (E2) were measured in blood samples from 45 patients with testicular tumors, 27 of whom had gynecomastia at some stage of their disease. Forty-two of the 45 patients had at least one abnormal hormone level. The most common abnormality was that of plasma estrone: it was elevated in 32 out of 42 (76%) patients in whom it was measured, suggesting a useful role for E1 as a testicular tumor marker. Prognosis was notably worse in patients with embryonal carcinoma, teratocarcinoma, and choriocarcinoma, in those with gynecomastia and, particularly, galactorrhea. Such patients also had the highest incidence of hormonal abnormalities as well as the most extreme absolute values. Hormonal mechanisms were implicated in the development of gynecomastia and galactorrhea. Prolactin, betahCG, E1, and E2 levels in all permutations correlated significantly among patients with gynecomastia, but not among those without, while estrogen to testosterone ratios were elevated in patients with galactorrhea.

Gonadal Steroids and Gonadotropins in Hyperthyroidism

Gynecomastia occurs in about 20 to 40 per cent of men with hyperthyroidism. Serum concentrations of total estradiol-17beta, total testosterone, and luteinizing hormone are supranormal in these patients. Serum concentration of SHBG is also high in hyperthyroidism. This can explain the high serum testosterone, essentially completely but not the high serum estradiol-17beta; thus, whereas serum unbound testosterone is normal, serum unbound estradiol-17beta is above normal in hyperthyroid men. This balance in relative concentrations of unbound gonadal steroids is apparently quite favorable to the development of gynecomastia in hyperthyroidism. Increased peripheral tissue metabolism of androgens to estrogens seems to be the major factor responsible for high estradiol-17beta in hyperthyroidism; increased glandular secretion of estradiol-17beta may also be important. The mechanism of hypomenorrhea or amenorrhea in hyperthyroidism remains unclear. Changes in circulating estrogens, androgens, and luteinizing hormone in hyperthyroid women are similar to those in hyperthyroid men. The mid-cycle ovulatory peak of luteinizing hormone may be blunted in patients with scanty periods whereas it may be altogether absent in those with amenorrhea.

Gynecomastia in patients immobilized in spica casts

Breast enlargement developed in five patients being treated with spica casts. Examination of the tissue excised in each case revealed gynecomastia. Previous reports of a relationship between long-term immobilization and the development of gynecomastia could not be found. Although evaluation of these patients revealed hormonal abnormalities, the pathophysiology of the growths remains an enigma.

Gynecomastia in Patients Immobilized in Spica Casts

Breast enlargement developed in five patients being treated with spica casts. Examination of the tissue excised in each case revealed gynecomastia. Previous reports of a relationship between long-term immobilization and the development of gynecomastia could not be found. Although evaluation of these patients revealed hormonal abnormalities, the pathophysiology of the growths remains an enigma.

Adrenocortical carcinoma with gynecomastia: a case report and review of the literature.

THE development of gynecomastia is an uncommon result of excessive steroid hormone production by adrenocortical tumors. The present report concerns the thirty-fourth occurrence of this phenomenon recorded in the world literature (1–16). The findings of relative adrenocortical insufficiency, increased excretion of estrogen-like materials in the urine and the successful isolation of steroids from the tumor (17) are of special interest in this patient. CASE REPORT A 28-year-old radio announcer noted the onset of intermittently tender nipples in March 1953 and of bilateral breast enlargement in September 1953. There was progressive increase in size during the next twelve months. The patient was sufficiently embarrassed by this cosmetic defect to request admission to the Salt Lake Veterans Administration Hospital in March 1955 for evaluation and treatment. He had noted a veiy gradual decline in libido and potency during the two years prior to admission. There were no other symptoms and no fluctuations in weigh...

Hormone excretion in liver disease and in gynecomastia.

GYNECOMASTIA occurs in 7 to 15 per 100,000 otherwise apparently normal adult men (1, 2). Transient gynecomastia is not uncommon in the new-born (3) and occurs during puberty in about 50 per cent of boys. It has been reported in association with the following diseases: adrenocortical tumors (4, 5, 6), chorioepitheliomas (7), other testicular tumors (8, 9), degeneration of the seminiferous tubules (10, 11), thyrotoxicosis (12), malnutrition (13, 14), paraplegia (15), and liver disease (16, 17, 18). It has been observed also following administration of desoxycorticosterone acetate (19), adrenal cortical extract (20), and testosterone (21, 22). The question may be raised as to whether or not the development of gynecomastia under these various circumstances is dependent on the operation of a common mechanism. Because of the influence of estrogen upon mammary ductal growth and the frequent occurrence of gynecomastia in men treated with, or otherwise exposed to estrogens, this hormone has been suspected to be in...