Methods for assessment, e.g., anthropometric indicators and imaging techniques, of several phenotypes of human obesity, with special reference to abdominal fat content, have been evaluated. The correlation of fat distribution with age, gender, total body fat, energy balance, adipose tissue lipoprotein lipase and lipolytic activity, adipose tissue receptors, and genetic characteristics are discussed. Several secreted or expressed factors in the adipocyte are evaluated in the context of fat tissue localization. The body fat distribution and the metabolic profile in nonobese and obese individuals is discussed relative to lipolysis, antilypolysis and lipogenesis, insulin sensitivity, and glucose, lipid, and protein metabolism. Finally, the endocrine regulation of abdominal visceral fat in comparison with the adipose tissue localized in other areas is presented.

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Subcutaneous and visceral adipose tissue : Their relation to the metabolic syndrome

Background and Methods Mutations in the estrogen-receptor gene have been thought to be lethal. A 28-year-old man whose estrogen resistance was caused by a disruptive mutation in the estrogen-receptor gene underwent studies of pituitary-gonadal function and bone density and received transdermal estrogen for six months. Estrogen-receptor DNA, extracted from lymphocytes, was evaluated by analysis of single-strand-conformation polymorphisms and by direct sequencing. Results The patient was tall (204 cm [80.3 in.]) and had incomplete epiphyseal closure, with a history of continued linear growth into adulthood despite otherwise normal pubertal development. He was normally masculinized and had bilateral axillary acanthosis nigricans. Serum estradiol and estrone concentrations were elevated, and serum testosterone concentrations were normal. Serum follicle-stimulating hormone and luteinizing hormone concentrations were increased. Glucose tolerance was impaired, and hyperinsulinemia was present. The bone mineral d...

https://www.nejm.org/doi/pdf/10.1056/NEJM199410203311604

Estrogen Resistance Caused by a Mutation in the Estrogen-Receptor Gene in a Man

https://www.gynecologiconcology-online.net/article/0090-8258(83)90111-7/pdf

Two pathogenetic types of endometrial carcinoma

One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common complex multifactorial human diseases. This challenge is partly due to the limitations of parametric-statistical methods for detection of gene effects that are dependent solely or partially on interactions with other genes and with environmental exposures. We introduce multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, to improve the identification of polymorphism combinations associated with disease risk. The MDR method is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., it assumes no particular inheritance model), and is directly applicable to case-control and discordant-sib-pair studies. Using simulated case-control data, we demonstrate that MDR has reasonable power to identify interactions among two or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control data set, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among four polymorphisms from three different estrogen-metabolism genes. To our knowledge, this is the first report of a four-locus interaction associated with a common complex multifactorial disease.

https://www.cell.com/ajhg/pdf/S0002-9297(07)61453-0.pdf

Multifactor-Dimensionality Reduction Reveals High-Order Interactions among Estrogen-Metabolism Genes in Sporadic Breast Cancer

https://www.fertstert.org/article/S0015-0282(08)01392-7/pdf

The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report

The purpose of the present study was to investigate the mechanisms by which estrogen production arises in the human female following the menopause. The possibilities considered were a) glandular secretion of estrone (E1) or estradiol (E2), b) the peripheral aromatization of circulating androstenedione (A), or c) the aromatization of other plasma precursors of estrone or estradiol. Studies were carried out in 6 postmenopausal women in which the following were measured: the plasma production rate of A (PRPA), the fraction of plasma androstenedione which was converted to estrone as measured in urine, and in blood, , and the total estrone production rate as measured by the urinary method (PRE1). The mean PRPA, 1.75 mg/24 hr, was about one-half of that observed in premenopausal women and arose principally from the adrenal glands. The mean transfer constant, value was 0.027, which is about twice the value obtained in premenopausal women, suggesting an increase in conversion of A to E1 with age. The results sugg...

Source of Estrogen Production in Postmenopausal Women

The formation by the gonads of [3H] testosterone from [7α-3H]pregnenolone and [1,2-3H] progesterone and the metabolism of [1,2-3H]testosterone by various tissues have been studied in 33 human fetuses that varied in age from phenotypically undifferentiated stages (1–3 cm crown-rump length) to sexually differentiated male and female embryos greater than 21 cm in length. In the first series of studies utilizing thinlayer and celite column chromatography for quantification of the metabolic products following incubation of the gonads with the C21 steroids, it was concluded that testosterone is the principal androgen formed by the fetal testis at the time of male sexual differentiation. The capacity for testosterone formation from these precursors was shown to rise from undetectable levels at 1–3 cm of development to maximal rates of about 150 pinoles/10 mg tissue/2 hr in the testes obtained from embryos of 7.1–9 cm crown-rump length, a sequence that correlates closely with the androgenmediated events ...

Testosterone Formation and Metabolism During Male Sexual Differentiation in the Human Embryo

Effect of obesity on conversion of plasma androstenedione to estrone in postmenopausal women with and without endometrial cancer

Overwhelming evidence has been accumulated which indicates that the placenta is the principal source of the greatly increased amounts of estrogen produced by pregnant women. This view received strong support from the elegant in vitro studies of Ryan, who first demonstrated net estrogen synthesis when testosterone or Δ4-androstenedione3 (1) and androst-5-ene-3β,16α,17β-triol (2) are incubated with placental preparations. Until recently, however, the exact sequence of the in vivo events which precede these final reactions has been unclear. The possible biochemical pathways and some of the important intermediates leading to the three classic estrogens, estrone, estradiol and estriol, are outlined in Fig. 1.

Placental estrogen biosynthesis during human pregnancy.

The purpose of the present study was to ascertain the relationship between aging and the extent of conversion of plasma androstenedione to estrone. Studies were carried out in 23 women and 26 men who weighed 130–180 pounds and 150–190 pounds, respectively, in which 3H estrone and 14C-androstenedione were administered intravenously and the transfer constant of plasma androstenedione to estrone as measured in urine, [ρ]AE1/BU, was determined. The results of these studies in both women and men demonstrate that with advancing age, there is a progressive and highly statistically significant increase in the efficiency with which circulating androstenedione is converted to estrone. The magnitude of the increase observed in the older subjects reached 2- to 4-fold that observed in the young adult.

Pentti K. Siiteri

Papers

Source of Estrogen Production in Postmenopausal Women

Testosterone Formation and Metabolism During Male Sexual Differentiation in the Human Embryo

Effect of obesity on conversion of plasma androstenedione to estrone in postmenopausal women with and without endometrial cancer

Placental estrogen biosynthesis during human pregnancy.

Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age.