The Role of Local Estrogen Biosynthesis in Males and Females

Simpson, Evan R.; Rubin, Gary; Clyne, Colin; Robertson, Kirsten; O’Donnell, Liza; Jones, Morris; Davis, Susan Ruth

doi:10.1016/s1043-2760(00)00254-x

Cited by 214 publications

(143 citation statements)

References 44 publications

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“…34,35,37,38 Involvement of oestrogen signalling in regulation of adipose tissue metabolism indicates a possible link between the effects of oestrogen and abdominal adiposity (male obesity), one of the main risk factors for OAC. 32,39,40 Moreover, a recent study suggests that OAC and Barrett's oesophagus cells respond to treatment with selective oestrogen receptor ligands, resulting in decreased cell growth and apoptosis. 40 Fat cells are a major source of endogenous oestrogen among postmenopausal women.…”

Section: Discussionmentioning

confidence: 99%

Hormone Replacement Therapy and Oral Contraceptives and Risk of Oesophageal Adenocarcinoma: A Systematic Review and Meta-analysis.

Lagergren

Brusselaers

2015

International Journal of Epidemiology

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There is an unexplained strong male predominance in the aetiology of oesophageal adenocarcinoma (OAC). The hypothesis that oestrogens are protective, deserves attention. A potential protective influence of exogenous oestrogen exposure, that is, hormone replacement therapy (HRT) and oral contraceptives (OC) has been addressed only in studies of limited statistical power, and the individual studies have not provided conclusive results. We conducted a systematic literature search and meta-analysis on HRT and OC and the risk of OAC. We used the databases PubMed and the Web of Science. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by the Mantel-Haenszel random-effect method. A total of five studies were included. Compared to never users, ever users of HRT had a statistically significantly decreased risk of OAC (pooled OR 5 0.75; 95% CI: 0.58-0.98), and ever users of OC had a borderline significantly decreased risk of this cancer (pooled OR 5 0.76; 95% CI: 0.57-1.00). In conclusion, HRT and OC use seems to be associated with a decreased risk of OAC. However, further research is warranted.Oesophageal adenocarcinoma (OAC) is up to nine times more common in men than women, yet the reasons behind this pattern remain unclear. 1,2 Gastro-oesophageal reflux and high body mass index (BMI), the two main risk factors for OAC, seem to influence the risk of developing OAC similarly in both genders, and might not explain the male predominance. [3][4][5][6] The typical male fat distribution, with mainly abdominal adiposity, is a stronger risk factor for OAC than BMI alone, 7 but it is uncertain if this exposure contributes the sex ratio of OAC. 8 It has also been hypothesised that female sex hormones, mainly oestrogen, are protective. This oestrogen hypothesis is supported by a 20-year delay in the onset of OAC in women compared to men, 9 and a particularly high male-to-female ratio during women's reproductive years. 10 Individual investigations of the potential role of exogenous hormonal therapy in women, including hormone replacement therapy (HRT) and oral contraceptives (OC), in the aetiology of OAC have failed to provide conclusive results. 11-15 The low incidence of OAC in women has hampered the statistical precision in the available studies. HRT is used to mitigate discomfort caused by decreased levels of circulating oestrogen and progesterone after menopause. Combined HRT includes both oestrogens and progesterone, and is recommended to women with an intact uterus, as it counteracts endometrial hyperplasia associated with oestrogen therapy. Oestrogen only HRT is recommended to women who have undergone hysterectomy. 16,17 The most commonly used OCs contain both oestrogen and progesterone. The often called 'mini pill' contains progesterone only, 18 and is recommended during breastfeeding as oestrogen reduces the amount of breast milk. 19 With the purpose of improving the knowledge of the relationship between HRT and OC exposure and risk of OAC, we conducted a systematic review and meta-analysis. Material a...

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Section: Discussionmentioning

confidence: 99%

Hormone Replacement Therapy and Oral Contraceptives and Risk of Oesophageal Adenocarcinoma: A Systematic Review and Meta-analysis.

Lagergren

Brusselaers

2015

International Journal of Epidemiology

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“…Only during pregnancy do these levels (0.13 M) approach those required for inhibition of the wild-type hGDH2 under base-line conditions. Whereas the levels of circulating estrogens in nonpregnant women are below those used here to inactivate hGDH2, there is evidence for extensive local biosynthesis in the central nervous system and other tissues and that this synthesis could raise estrogen to levels higher than those of serum (30). In the brain, astrocytes, the cells that express hGDH2, are the only neural cells capable of synthesizing estrogens from androstenedione (31); they express both 17␤-hydroxysteroid dehydrogenase and P450-aromatase.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Modification of Human Glutamate Dehydrogenases Is Linked to Enzyme Activation State

Borompokas

Papachatzaki

Kanavouras

et al. 2010

Journal of Biological Chemistry

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Mammalian glutamate dehydrogenase (GDH) is a housekeeping enzyme central to the metabolism of glutamate. Its activity is potently inhibited by GTP (IC 50 ‫؍‬ 0.1-0.3 M) and thought to be controlled by the need of the cell in ATP. Estrogens are also known to inhibit mammalian GDH, but at relatively high concentrations. Because, in addition to this housekeeping human (h) GDH1, humans have acquired via a duplication event an hGDH2 isoform expressed in human cortical astrocytes, we tested here the interaction of estrogens with the two human isoenzymes. The results showed that, under base-line conditions, diethylstilbestrol potently inhibited hGDH2 (IC 50 ‫؍‬ 0.08 ؎ 0.01 M) and with ϳ18-fold lower affinity hGDH1 (IC 50 ‫؍‬ 1.67 ؎ 0.06 M; p < 0.001). Similarly, 17␤-estradiol showed a ϳ18-fold higher affinity for hGDH2 (IC 50 ‫؍‬ 1.53 ؎ 0.24 M) than for hGDH1 (IC 50 ‫؍‬ 26.94 ؎ 1.07 M; p < 0.001). Also, estriol and progesterone were more potent inhibitors of hGDH2 than hGDH1. Structure/function analyses revealed that the evolutionary R443S substitution, which confers low basal activity, was largely responsible for sensitivity of hGDH2 to estrogens. Inhibition of both human GDHs by estrogens was inversely related to their state of activation induced by ADP, with the slope of this correlation being steeper for hGDH2 than for hGDH1. Also, the study of hGDH1 and hGDH2 mutants displaying different states of activation revealed that the affinity of estrogen for these enzymes correlated inversely (R ‫؍‬ 0.99; p ‫؍‬ 0.0001) with basal catalytic activity. Because astrocytes are known to synthesize estrogens, these hormones, by interacting potently with hGDH2 in its closed state, may contribute to regulation of glutamate metabolism in brain.

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“…In the human male, estrogens, in particular the bioavailable fraction, decline with advancing age (22) together with the progressive fall in testosterone (32,33), but estradiol remains twofold higher in normal older men if compared with postmenopausal women whose estradiol levels range from 36 to 73 pmol/l (10 -20 pg/ml) (34). Thus, a relative estrogen deficiency also occurs in normal older men as a consequence of aging, but it generally remains less severe than in postmenopausal women since the testes continue to produce a sufficient amount of androgen for peripheral and local conversion into estro-gens (35,36), while the cessation of ovarian function in women leaves only a very small quota of circulating androgens coming from adrenal secretion (37). Severe estrogen deficiency occurs in aging men when a severe degree of hypogonadism occurs.…”

Section: Estradiol and Age-related Male Osteoporosismentioning

confidence: 99%

Osteoporosis and male age-related hypogonadism: role of sex steroids on bone (patho)physiology

et al. 2006

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Male age-related bone loss is caused, at least in part, by hypogonadism that occurs with advancing age. The study of the effects of sex steroids on bone physiology in men has recently highlighted the central role of estrogens on bone pathophysiology. This review focuses on particular aspects of bone physiology and pathophysiology in aging men, noting both the similarities to and the differences from female counterparts. In particular, the role of sex steroids on bone sexual dimorphism in health and disease has been analyzed.

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The Role of Local Estrogen Biosynthesis in Males and Females

Cited by 214 publications

References 44 publications

Hormone Replacement Therapy and Oral Contraceptives and Risk of Oesophageal Adenocarcinoma: A Systematic Review and Meta-analysis.

Hormone Replacement Therapy and Oral Contraceptives and Risk of Oesophageal Adenocarcinoma: A Systematic Review and Meta-analysis.

Estrogen Modification of Human Glutamate Dehydrogenases Is Linked to Enzyme Activation State

Osteoporosis and male age-related hypogonadism: role of sex steroids on bone (patho)physiology

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