Letter: Natural oestrogen replacement therapy and blood clotting.

Abstract

coefficients for the three subjects are 0 019, 0-029, and 0-024 respectively. While these show statistically significant differences (P< 0-05), they are small enough to be accounted for by the likely differences in albumin: globulin ratio between subjects rather than any genuine differences in albumin binding, for the cuffing method measures binding by all proteins, and globulin cannot be ignored.3The important question is whether individual determination of a binding coefficient by the proposed method will give a better correction for total protein binding of calcium than would the more straightforward use of average population coefficients for albumin and globulin. The within-subject coefficients of variation for the authors' three subjects arerage 12%, but a computer simulation of the four-point binding method which incorporates the authors' coefficients of variation for calcium and albumin analyses suggests that even this is likely to be too favourable an estimate. The analysis (see reporting the results of a double-blind crossover trial of equine ("natural") oestrogens against placebo in the treatment of 30 patients with menopausal symptoms (18 October, p 139) recorded raised plasma levels of the extrinsic clotting factors VII and X and accelerated prothrombin time after three months' treatment with conjugated equine oestrogens (Premarin 1-25 mg daily). We have recently completed investigations of the effects of both "natural" and syn.thetic oestrogens on climacteric symptoms, blood biodhemistry, and blood clotting in perimenopausal patients.' We similarly found a significant increase in the levels of factors X and VII and accelerated prothrombin times in patients who had received either conjugated equine oestrogens (1-25 mg daily) or ethinyloestradiol (0 03 mg daily) for three months.However, the study of Dr Coope and her colleagues was confined to evaluating equine "natural" oestrogens and their findings imply that other "natural" oestrogens might also accelerate blood clotting factors. Such a conclusion would be at variance with our own data, obtained in a double-4blind, betweenpatient study over six months of the effects of oestrone piperazine sulphate (Harmogen, 3-0 mg daily), ethinyloestradiol (0 03 mg daily), and placebo in 60 perimenopausal patients. At each monthly assessment tests of blood clotting and platelet studies were performed, of which the following are relevant to the present communication: prothrornbin time (BCR)2; platelet aggregation time; fibrinogen assay3; cephalin time; and assays of factors X4 and VII.5Of 79 patients admitted, 60 completed the six-month trial: eight of the 19 withdrawn developed adverse effects to the active treatments and 10 patients receiving placebo were withdrawn because of failure to control the severity of menopausal symptoms. The results of coagulation studies are shown in the accompanying table. Significant increases (P<005) in the levels of fibrinogen and factors VII and X and acceleration (P<0 01) in prothrombin, cephalin, and platelet aggregation times...

A Comparative Longitudinal Study on Sex Hormone Binding Globulin Capacity During Estrogen Replacement Therapy

“…Thus, considering the dosage, ethinyl-estradiol in this system was approximately 120 times as potent as the natural estrogens. This estimate is in agreement with previous observations on the effect on blood coagulation (2).…”

Estrogen Induction of Liver Proteins and High-Density Lipoprotein Cholesterol: Comparison between Estradiol Valerate and Ethinyl Estradiol

“…The estrogenic potency of different prepa rations may vary considerably depending on which biological system is studied [7,9,10,26]. An estimate of the relative potency of ethinyl estradiol and estradiol valerate for the different parameters of the present study is given in table II.…”

“…Estrogens are rapidly absorbed from the intestine and dur ing the first liver pass hepatic cells are ex posed to unphysiologically high steroid con centrations. Estrogen levels in the portal vein may be 4-5 times higher than in the general circulation [24] and the effects of oral estro gens upon the liver may also be related to adverse effects [6][7][8][9].…”

“…This effect has been related to alterations in the serum lipoprotein profile and especially to the increased concentrations of high-density lipoprotein (HDL) cholesterol during therapy [1,2], The route of adminis tration is important in this respect since oral estrogen therapy will increase the serum con-centration of several estrogen-sensitive liver proteins, including HDL subfractions in a dose-dependent manner, while there is no such effect when equipotcnt amounts of estro gen are given parenterally [3][4][5], On the other hand the enhanced liver metabolism follow ing oral estrogen administration may also be related to unwanted side effects like hyperten sion [6], venous thromboembolism [7][8][9] and gallbladder disease [8],…”