2-Hydroxyestrone induced rise in serum luteinizing hormone in the immature male rat

Naftolin, Frederick; Morishita, Hajime; Davies, I. John; Todd, Roberta B.; Ryan, Kenneth J.; Fishman, Jack

doi:10.1016/0006-291x(75)90133-3

Cited by 112 publications

(24 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this context, the analogy between drugs and hormones extends further because many of the metabolites of natural steroid hormones, like those of numerous drugs, have been shown to exert potent biological actions independent of, and sometimes distinctive from, those of their parent compounds (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52). Thus, nutrition-induced alterations of specific steroid biotransformations that are mediated by enzymes in the liver, and possibly in other tissues, have the potential for substantially modifying the biological impact of these hormones in humans.…”

Section: Discussionmentioning

confidence: 99%

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

Kappas¹,

Anderson²,

Conney³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The in vivo biotransformations of drugs known to be metabolized by enzymes localized in the endoplasmic reticulum of liver can be greatly altered by diet in humans, as we have shown previously. Steroid hormones also are metabolized extensively by hepatic microsomal enzymes; therefore, we examined the possibility that testosterone and estradiol biotransformations, as assessed with radiolabeled tracer methods, could be influenced by dietary macronutrients. Normal males were fed a high-protein diet for 2 weeks, followed by a high-carbohydrate diet for an additional 2 weeks. The A4-5a-reduction of testosterone was considerably diminished, while the cytochrome P-450-dependent hydroxylation of estradiol at the C2 position was substantially enhanced during ingestion of the high-protein diet as compared with the high-carbohydrate diet. These results indicate that dietary macronutrients can significantly alter major metabolic pathways for testosterone and estradiol in man. The mechanism by which reciprocal changes in the A4-5a-reduction of testosterone and the cytochrome P-450-mediated oxidation of estradiol are produced by diet is not known. Similar changes in steroid A4-5a-reduction and cytochrome P-450-dependent chemical oxidations have been observed in circumstances in which the mixed-function oxidase system in liver is induced by agents such as phenobarbital, hexachlorobenzene, dioxin, and polyhalogenated biphenyls. Thus, the alterations in steroid hormone metabolism produced by dietary macronutrients in man mimic those that can be produced by drugs and environmental chemicals.The oxidative metabolism of drugs can be greatly influenced by specific components of the human diet, as studies from our laboratories have shown (1-8). These studies demonstrated that feeding humans cruciferous vegetables (5), charcoal-broiled beef (6-8), or a high-protein/low-carbohydrate diet (1-4) stimulates the metabolism of certain drugs by the microsomal cytochrome P-450-dependent mixed-function oxidase system. Natural steroid hormones, like many drugs and other foreign chemicals, also undergo biotransformations mediated by microsomal enzymes (9-12); therefore, it was of interest to determine whether the dietary content of protein and carbohydrate could alter the metabolism of such hormones in humans. The major sex steroids, testosterone and estradiol, were chosen for study because cytochrome P-450-dependent oxidation is the principal metabolic fate of the latter compound (12, 13), whereas reduction by a microsomal A4-5a-reductase represents a primary biotransformation for the androgen (14). Thus by changing, in a carefully controlled fashion, the dietary intakes of protein and carbohydrate in the same individuals, the role of specific nutritional factors in determining the metabolic fate of these steroid hormone substrates of microsomal enzymes could be determined. The metabolism of antipyrine also was studied because the effects of protein and carbohydrate in the diet on the oxidative disposition of this cytochrome P-450 subs...

show abstract

Section: Discussionmentioning

confidence: 99%

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

Kappas¹,

Anderson²,

Conney³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Liver disease [Zumoff et al, 1968], and less consistently, breast cancer [Zumoff et al, 1966;H ellman et al, 1971], are both associated with increased 16« and decreased 2-hydroxylation. More recently, it was found that young women who were malnourished due to anorexia nervosa exhibited significant increases of 2-hydroxylation of estradiol relative to normal or obese individuals [Fishman et al, 1975], indicating an influence of body weight or composition on estradiol metabolism and raising the possibility that the catechol estrogens may play a role in this disease.…”

mentioning

confidence: 99%

The Catechol Estrogens

Fishman¹

1976

Neuroendocrinology

View full text Add to dashboard Cite

“…The 16a-hydroxyestrogens-estriol and 16a-hydroxyestrone-demonstrate uterotropic activity comparable to that of the parent hormone, estradiol (12, 13). On the other hand, the principal 2-hydroxyestrogens-2-hydroxyestrone and 2-methoxyestrone exhibit virtually no peripheral estrogenic effects but appear to play a regulatory role in neuroendocrine mediated events (14,15).Numerous studies have examined and compared the urinary estrogen metabolite patterns in women with breast cancer and normal subjects but these have yielded conflicting and inconclusive findings (4, 10). However, the results of these investigations were subject to inaccuracies inherent in the methods used, so that the issue ofaberrant estrogen metabolism in breast cancer remained unresolved.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Abnormal oxidative metabolism of estradiol in women with breast cancer.

Schneider¹,

Kinne²,

Fracchia³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

215

106

View full text Add to dashboard Cite

The three dominant oxidative biotransformations of estradiol were examined in 10 normal women and 33 females with breast cancer by using a recently devised radiometric method. Estradiol tracers, labeled with 3H specifically in the 17a, C-2, or 16a position, were used to measure both the rate and extent of 17P-ol oxidation (the initial metabolic step) and the subsequent 2-and 16a-oxidative reactions. The mean ± SEM values for the extent of estradiol metabolism at these three specific sites were 76.9 ± 5.3%, 31.1 ± 4.0%, and 9.3 ± 0.8%, respectively, in normal subjects. Corresponding data in patients with breast cancer-i.e., 73.0 ± 4.2%, 32.7 ± 2.7%, and 14.9 ± 1.5%-revealed a significantly greater extent of 16a-hydroxylation in the latter population. Because the 16a-hydroxylated compounds (including estriol) are themselves potent estrogens, these changes may have important hyperestrogenic consequences that could have a bearing on the etiology of the disease.Endocrine factors have been implicated in the initiation or promotion, or both, of mammary tumorigenesis based on data collected from several sources. These include both experimental studies using animal models and epidemiological and clinical investigations in human subjects (1). Thus, certain features of the menstrual history and age at parity, which can lengthen the period ofexposure to estrogens secreted by the ovaries, appear to be associated with an increased risk for the disease (2, 3). On the other hand, oophorectomy prior to age 35 can lessen the risk of breast cancer (3). Because an augmentation in estrogen secretion could be implicated in the etiology of the human disease, numerous studies have been conducted to detect such an increase in women with, or at high risk to develop, breast cancer (4). Although some investigators have reported significant differences in urinary or plasma estrogen levels, or both, between these subjects and normal individuals (5-7), these findings have not been consistent and have been challenged by others (8, 9). An alternative and possibly more viable hypothesis that an alteration in estrogen metabolism is associated with breast cancer (4, 10) has also been the subject of extensive investigations.The metabolism of estradiol, which is primarily oxidative, consists ofan initial oxidation ofthe 17/3-hydroxy group to yield estrone. This steroid is subsequently metabolized mainly through either of two alternate hydroxylative pathways; namely, hydroxylation at the C-2 or the 16a position (11). These hydroxylations are of particular interest in that they constitute competing reactions whose products are themselves active compounds characterized by markedly different biological properties. The 16a-hydroxyestrogens-estriol and 16a-hydroxyestrone-demonstrate uterotropic activity comparable to that of the parent hormone, estradiol (12, 13). On the other hand, the principal 2-hydroxyestrogens-2-hydroxyestrone and 2-methoxyestrone exhibit virtually no peripheral estrogenic effects but appear to play a regulatory role in neur...

show abstract

2-Hydroxyestrone induced rise in serum luteinizing hormone in the immature male rat

Cited by 112 publications

References 22 publications

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

The Catechol Estrogens

Abnormal oxidative metabolism of estradiol in women with breast cancer.

Contact Info

Product

Resources

About