Synthesis of catechol estrogens by human uterus and leiomyoma

Reddy, V. R.; Hanjani, Parviz; R, Rajan

doi:10.1016/s0039-128x(81)80017-7

Cited by 40 publications

(17 citation statements)

References 25 publications

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“…As ULMs are oestrogen dependent, a higher frequency of occurrence would be associated with the COMT Val/Val genotype than the low oestrogenic Met/Met genotype. In agreement with this hypothesis were the findings of Reddy et al, 33 who demonstrated lower levels of 2-hydroxy oestradiol in leiomyomas compared with adjacent normal myometrium and implicated this in the tumourgenesis. In the same context, two reports in American 34 and Finnish 27 populations described a significantly decreased risk of breast cancer in premenopausal women with a COMT Met/Met genotype.…”

Section: Comtsupporting

confidence: 72%

Molecular genetics and racial disparities of uterine leiomyomas

Othman

Al-Hendy

2008

Best Practice & Research Clinical Obstetrics & Gynaecol

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Uterine leiomyomas (ULMs) are benign oestrogen-dependent tumours of the myometrium. They are the most common tumours of the female genital tract, affecting around 77% of the female population. ULMs are more common in Black women than White women. These tumours tend to develop earlier and be more numerous, larger in size and more symptomatic in Black women than other ethnic groups. The molecular mechanism underlying this ethnic disparity is not fully understood. Polymorphism of genes involved in oestrogen synthesis and/or metabolism (COMT, CYP17), variation in the expression levels or function of oestrogen and progesterone receptors or retinoic acid nuclear receptors (retinoid acid receptor-α, retinoid X receptor-α), or aberrant expression of micro-RNAs are some of the molecular mechanisms that may be involved. Keywords molecular genetics; race; leiomyomaUterine leiomyomas (ULMs) are benign, monoclonal tumours of the smooth muscle cells of the myometrium. They are composed of large amounts of extracellular matrix containing collagen, fibronectin and proteoglycan. 1 ULMs may cause significant morbidity through their presence in the uterus and pelvic cavity. These benign tumours are a significant cause of pelvic pain, abnormal uterine bleeding, infertility and pregnancy complications. 2 ULMs are the most common tumours of the female genital tract. Serial sectioning at 2-mm intervals of 100 consecutive total hysterectomy specimens revealed the presence of leiomyomas in 77% of cases. 3 The rate of hospitalization of women for ULMs is 3.0 per 1000 women-years in the USA. Around 200 000 hysterectomies and 30 000 myomectomies Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access OESTROGEN DEPENDENCY OF ULMSThere is plenty of clinical and research evidence that ULMs are oestrogen-dependent tumours. The risk of developing ULMs increases with age during the premenopausal years; however, tumours typically regress and/or become asymptomatic with the onset of menopause. 6 Obesity, age at menarche and unopposed oestrogen exposure have been linked to an increased risk of ULMs, and cigarette smoking, use of oral contraceptives and parity have been identified as protective factors. 7 Moreover, using gonadotrophin-releasing hormone agonists leads to shrinkage of ULMs through the suppression of ovarian oestrogen production to postmenopausal levels. 8 At the molecular level, primary ULM cells express oestrogen receptors (OR) and progesterone receptors (PR). Rodent leiomyoma cells derived from the Eker rat model for this disease proliferate in response to oestrogen in cult...

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Section: Comtsupporting

confidence: 72%

Molecular genetics and racial disparities of uterine leiomyomas

Othman

Al-Hendy

2008

Best Practice & Research Clinical Obstetrics & Gynaecol

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“…It is well established that estrogen (E) metabolites play a critical role in many E-related tumors (3). Earlier studies have suggested that endogenous levels of catechol Es are significantly different from ULM and adjacent normal myometrium (4). Consequently, it is conceivable to expect that regulation of E-metabolizing genes might have an etiologic role in the development of ULM.…”

mentioning

confidence: 99%

Hormonal regulation of catechol-O-methyl transferase activity in women with uterine leiomyomas

Salama¹,

Ho²,

Wang³

et al. 2006

Fertility and Sterility

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“…In contrast, 2-hydroxy estradiol and 4-hydroxy estradiol in the proliferative human endometrium were formed in equal amounts (45). Thus, the extent of 2and 4-hydroxylation of an estrogen may be dependent on the structure.…”

Section: In Vitro Metabolism Of Ring B Unsaturated Equine Estrogensmentioning

confidence: 91%

Pharmacokinetics and Pharmacodynamics of Conjugated Equine Estrogens: Chemistry and Metabolism

Bhavnani¹

1998

Experimental Biology and Medicine

113

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Conjugated equine estrogens (Premarin), are used extensively for estrogen replacement therapy and prevention of osteoporosis and cardiovascular disease in postmenopausal women. Premarin contains at least 10 estrogens that are the sulfate esters of the ring B saturated estrogens: estrone, 17beta-estradiol, 17alpha-estradiol, and the ring B unsaturated estrogens: equilin, 17beta-dihydroequilin, 17alpha-dihydroequilin, equilenin, 17beta-dihydroequilenin, 17alpha-dihydroequilenin, and delta-8-estrone. Bioassays and estrogen receptor binding studies indicate that all 10 estrogens are biologically active. Moreover, individual components, such as equilin sulfate, delta-8-estrone sulfate, 17beta-dihydroequilin sulfate and estrone sulfate, have potent estrogenic effects. Estrogen sulfates can be absorbed directly from the gastrointestinal tract; however, hydrolysis of the sulfates also occurs in the gastrointestinal tract, and the unconjugated estrogens formed are readily absorbed. After absorption, these estrogens are sulfated rapidly and circulate in this form. The pharmacokinetics of these estrogens indicate that the unconjugated estrogens are cleared from the circulation at a faster rate than their sulfate ester forms. In postmenopausal women, the 17-keto derivatives of these estrogens are metabolized to the more potent 17beta-reduced products. The extent of this activation is nearly 10 times higher with some ring B unsaturated estrogens. The 17beta-reduced metabolites are cleared from the blood at a slower rate than their corresponding 17-keto derivatives. In the human endometrium, equilin is metabolized to 2-hydroxy and 4-hydroxy equilin, with 2-hydroxylation being predominant. In contrast, 2-hydroxy and 4-hydroxy estradiol are formed in equal amounts. Similarly, 16alpha-hydroxylation occurs with both types of estrogens; however, with the ring B saturated estrogens, the 17-keto steroid 16alpha-hydroxy estrone was the major urinary metabolite, whereas with the ring B unsaturated estrogens, the 17beta-reduced steroids, such as 16alpha-hydroxy-17beta-dihydroequilin and 16alpha-hydroxy-17beta-dihydroequilenin, were the major metabolites. This difference in metabolism may be important as it has been suggested that 16alpha-hydroxy estrone (alpha-ketol structure) can form covalent adducts with macromolecules and that it may be oncogenic. These types of interactions will not occur with the 16alpha-hydroxylated-17beta-reduced metabolites of ring B unsaturated estrogens. Since all of the estrogens present in Premarin have estrogenic activity, the pharmacological effects of Premarin are a result of the sum of these individual activities. Therefore, preparations lacking some of these important components may not offer the same degree of beneficial effects as Premarin.

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Synthesis of catechol estrogens by human uterus and leiomyoma

Cited by 40 publications

References 25 publications

Molecular genetics and racial disparities of uterine leiomyomas

Molecular genetics and racial disparities of uterine leiomyomas

Hormonal regulation of catechol-O-methyl transferase activity in women with uterine leiomyomas

Pharmacokinetics and Pharmacodynamics of Conjugated Equine Estrogens: Chemistry and Metabolism

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