Clare D. Edman

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

The purpose of this study was to ascertain if a relationship exists between the transfer constant of conversion of plasma androstenedione to estrone ([rho]AE1BU) and total body weight or excessive body weight in 50 postmenopausal women, of whom 25 had adenocarcinoma of the endometrium and 25 had no endometrial disease. The [rho]AE1BU ranged from 0.015 to 0.129 in these 50 women. The [rho]AE1BU in the women with endometrial cancer was 0.051 +/- 0.006 (mean +/- S.E.), whereas that in the women with no endometrial disease was 0.039 +/- 0.004. These values are not significantly different (p greater than 0.05). The body weights of these 50 women ranged from 104 to 430 pounds. The weight of the patients with endometrial cancer was 234 +/- 16 pounds (mean +/- S.E.), and that for the women with no endometrial disease was 194 +/- 12 pounds. A statistically significant correlation (p less than 0.001) was found between [rho]AE1BU and body weight and between [rho]AE1BU and excessive body weight in both groups of women. Moreover, obesity and aging appear to act in concert to potentiate the conversion of plasma androstenedione to estrone in extraglandular sites since the [rho]AE1BU is considerably greater among obese postmenopausal women than among comparably obese premenopausal women.

Plasma Precursors of Estrogen

The utilization of plasma dehydroisoandrosterone for estrogen production was studied in 4 normal young nonpregnant women and in one young surgical castrate woman. The mean transfer constant for total conversion to estrogen, [∑]DEBU’ was 0.0016 of which about one third (0.0005) could be accounted for by conversion of dehydroisoandrosterone first to plasma androstenedione which in turn was converted to estrone. The remaining fractional conversion appeared to result principally in estradiol formation via a pathway probably not involving plasma androstenedione. The conversion of plasma dehydroisoandrosterone to estrogen was similar in the surgical castrate to that observed in the ovulating women. It is concluded that plasma dehydroisoandrosterone is converted to estrogen at extraglandular site(s) but this contribution represents only a minor fraction of total estrogen production in normal young women.

A prospective randomized study of pregnancy rates following intrauterine and intracervical insemination using frozen donor sperm

Cryopreserved sperm have lowered fertility when compared with fresh sperm in artificial insemination by donor programs. The purpose of this study was to compare pregnancy rates following intrauterine insemination (IUI) and intracervical insemination (ICI) with cryopreserved sperm in a prospective trial using the patient as her own control. A total of 154 patients were randomized into alternating treatment cycles and underwent 238 cycles of IUI and 229 cycles of ICI. The pregnancy rate per treatment cycle was 9.7% following IUI and 3.9% following ICI. Treatment outcome was influenced by patient age, ovulatory status, and endometriosis. Pregnancy success correlated well with the post-thaw survival of sperm and the number of motile cells inseminated. In spite of having normal semen parameters, some donors were found to have markedly reduced sperm fecundity. We conclude that IUI with cryopreserved sperm can be an effective treatment for couples with infertility, genetic indications, or other reasons.

Massive Extraglandular Aromatization of Plasma Androstenedione Resulting in Feminization of a Prepubertal Boy

This report describes the mechanism of origin and the quantity of estrogen produced in a prepubertal boy who developed severe feminization at 8 yr of age as the result of a heretofore undescribed metabolic abnormality. The clinical findings were gynecomastia and accelerated linear growth and bone maturation. At the time feminization developed, there were no signs of growth or development of the otherwise normal prepubertal male external genitalia or any increase of muscle mass that normally accompanies male puberty. The hyperestrogenism was found to be the consequence of massive extraglandular conversion of plasma androstenedione to estrone. During a 6-mo period of study, the plasma production rate of androstenedione ranged from 1.2 to 1.6 mg/day. More than 55% of plasma androstenedione was metabolized by aromatization to estrone which, in turn, was extensively sulfurylated in the tissue sites of aromatization before its entry into the blood. Thus, estrone sulfate was the final product in the aromatizing sites, and the plasma production rate of estrone sulfate derived from plasma androstenedione was 782 mug/24 h. The extent of extraglandular conversion of plasma androstenedione to estrone measured in this boy was 50 times that observed in two normal prepubertal boys. Moreover, 94% of the extraglandular aromatization occurred in extrahepatic sites. The metabolic clearance rate of plasma androstenedione, 2,380 liters/day per m(2), was markedly increased in this boy. Approximately 1,500 liters of plasma androstenedione clearance was accounted for by extrahepatic, extraglandular aromatization. The fractional conversion of testosterone to estradiol, 0.16, was 50 times greater in this boy than that observed in normal young adult men. The total extent of aromatization of plasma prehormones was even greater in this boy inasmuch as evidence was obtained that aromatization of 16-hydroxysteroids, e.g. 16alpha-hydroxy androstenedione and 16alpha-hydroxy dehydroisoandrosterone (sulfate), resulted in estriol formation independent of estrone formation. Thus, extensive extrahepatic, extraglandular aromatization resulted in advanced feminization in this prepubertal boy by a previously undescribed metabolic abnormality.

Identification of the estrogen product of extraglandular aromatization of plasma androstenedione

Abstract The purpose of these studies was (1) to determine the duration of urine collection needed for complete excretion of radiolabeled metabolites of estrone following the infusion of ( 3 H)-estrone and ( 14 C)-androstenedione; (2) to compare the transfer constant of conversion of plasma androstenedione to plasma estrone measured from the 3 H: 14 C ratio of plasma estrone [ ϱ ] BU AE1 after four hours of tracer infusion to the [ ϱ ] BU AE1 computed from the 3 H: 14 C ratio of urinary estrone; and (3) to determine the duration of tracer infusion required to achieve steady-state conditions in the 3 H: 14 C ratio of plasma estrone when ( 3 H)-estrone and ( 14 C)-androstenedione are infused into obese and nonobese women. We found that the 3 H: 14 C ratios of urinary estrone, estradiol, and estriol are very similar when urine collections are complete and obtained for a sufficient time to allow complete excretion of both ( 3 H)-estrone metabolites and ( 14 C)-estrone metabolites. The rate of urinary excretion of the estrone metabolites is slower in obese subjects than in nonobese subjects. Four-hour infusions of ( 3 H)-estrone and ( 14 C)-androstenedione are insufficient to obtain steady-state conditions in the concentrations of plasma ( 3 H)-estrone and plasma ( 14 C)-estrone derived from infused ( 14 C)-androstenedione. The time required to reach steady-state conditions varies directly with body weight. In thin individuals, seven hours of tracer infusion may be sufficient to reach steady-state conditions when ( 3 H)-estrone and ( 14 C)-androstenedione are infused; whereas, 48 hours of infusion may be necessary to achieve these same conditions in morbidly obese individuals. When the time of infusion required to reach an equilibrium between ( 14 C)-estrone derived from infused ( 14 C)-androstenedione and ( 3 H)-estrone in plasma is analyzed as a function of body weight, a highly significant correlation (p

Placental clearance rate of maternal plasma androstenedione through placental estradiol formation: An indirect method of assessing uteroplacental blood flow

The metabolism of androstenedione (A) by the placenta in late pregnancy and the early puerperium was studied. The metabolic clearance rate of A (MCR-A) was increased in pregnant women, 2,825 +/- 207 L/24 hr (mean +/- SEM), compared to 2,020 +/- 140 L/24 hr in nonpregnant women of similar body weight. The immediate puerperal MCR-A was 2,538 +/- 50 L/24 hr. Therefore, approximately 10% of maternal plasma A was cleared by the placenta. In the latter half of pregnancy, the extent of conversion of maternal plasma A through estradiol formation, (rho)AE2, was increased, whereas in the immediate puerperium it was normal, 0.018. Moreover, 90% of aromatase activity was attributed to the placenta in late pregnancy. From these data, we computed that the placental clearance rate of A through estradiol (PCAE2) from whole blood was 497 +/- 41 ml/min in women with a single fetus and 691 +/- 102 ml/min in women with twin fetuses. Thus, it appears that the PCAE2 is a sensitive index of maternal-placental perfusion.

Kallmann syndrome associated with choanal atresia

Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. A previously unreported association of Kallmann syndrome and choanal atresia in a family is reported. The mechanism of the embryopathic association of hypogonadotropic hypogonadism, anosmia, and choanal atresia is thought to be due to a single developmental field defect in the region of the median forebrain and associated structures. An irregular autosomal dominant mode of inheritance is suspected.

An assay for human erythrocyte catechol-o-methyltransferase activity using a catechol estrogen as the substrate

A radiometric assay for catechol-O-methyltransferase (COMT) activity in human erythrocytes is described that employs 2-hydroxy[3H]estrone, and non-radiolabeled S-adenosylmethionine (SAM) as the cosubstrates. The ease of separation of the product of the reaction, 2-methoxy[3H]estrone from 2-hydroxy[3H]estrone makes it possible to achieve low reaction blanks. The assay is very sensitive, and only 200 microliter of whole blood are used per determination. The assay is highly reproducible. The interassay variability (coefficient of variation) was 6.5% for 24 assays of COMT activity in red blood cells in blood obtained daily for 24 days from one person. In incubations conducted at 37 degrees C for 30 min, the catechol-O-methyltransferase activity was a linear function of enzyme concentration (equivalent to 11 to 180 microliter of packed red blood cells). Employing this assay, we evaluated the catalytic conversion of 2-hydroxyestrone to 2-methoxyestrone by catechol-O-methyltransferase from human red blood cells and found that the apparent Michaelis constant and the apparent maximal rate of reaction were 3 x 10(-7) M and 6.7 x 10(-9) mol . ml-1 erythrocytes . h-1, respectively. The catechol-O-methyltransferase activity measured in erythrocytes obtained from 100 healthy subjects (men and nonpregnant women) was 8.2 +/- 0.17 (mean +/- S.E.) nmol 2-methoxyestrone . ml-1 erythrocytes . h-1.

Catechol-O-methyltransferase activity in erythrocytes of pregnant women.

Catechol-O-methyltransferase (COMT) is the enzyme that converts catechols, e.g., catecholamines and catechol estrogens, to their methyl ethers. COMT activity measured in erythrocytes (RBCs) of healthy men (No. = 47) and healthy nonpregnant women (No. = 53) was 8.2 +4- 0.17 nmoles X ml.-1 (mean and standard error). The COMT activity in RBCs of healthy pregnant women (No. = 100) was 10.7 +/- 0.29 nmoles X ml.-1 RBC X hr.-1, a value which is significantly higher than that found in RBCs of men and nonpregnant women (p less than 0.001).

Catechol-O-methyltransferase activity in erythrocytes of women taking oral contraceptive steroids

We have measured catechol-O-methyltransferase (COMT) activity in erythrocytes (red blood cells, RBCs) obtained from 64 women taking oral contraceptives steroids and compared these values with those found in RBCs obtained from 73 women using nonsteroidal contraceptives. The COMT activity in the RBCs of women taking oral contraceptives steroids and of women not taking contraceptive steroids was 9.1 +/- 0.28 (mean and standard error) and 8.8 +/- 0.26 nmoles 2-methoxyestrone X ml-1 RBC X hr-1, respectively. This difference in the COMT activity in RBCs from these two groups of women was not statistically significant. This finding differs from that of others who found that COMT activity in RBCs of women taking oral contraceptive steroids was greater than that of women not taking such drugs.