The Effects of Postmenopausal Hormone Replacement Therapy and Oral Contraceptives on the Endogenous Estradiol Metabolism

Abstract

The estradiol metabolism may be of clinical relevance in the pathophysiology of various diseases; the increase in D-ring metabolites over A-ring metabolites in breast cancer patients is of special interest. Since estrogen therapy has been blamed for increasing the risk of breast cancer, the effects of hormonal replacement therapy (HRT) and oral contraception were investigated on the ratio of the main D-ring metabolite, 16alpha-hydroxyestrone (16-OHE1), to the main A-ring metabolite, 2-hydroxyestrone (2-OHE1). In our study, hormone replacement therapy (HRT) in postmenopausal women consisted of administration of estradiol valerate either with or without addition of the progestin dienogest. In the second part of the study, women of reproductive age received ethinylestradiol plus dienogest or ethinylestradiol plus norethisterone acetate as oral contraceptives (OC). 2-OHE1 and 16-OHE1 were measured by enzyme immunoassay in 8 h night-urine collected before and after 3 months of hormone administration. With HRT, that is, estradiol valerate or estradiol valerate plus dienogest, the ratios before treatment were 0.47 and 0.60; after 3 months, they were 0.54 and 0.52, respectively. There were no significant differences. With oral contraception, that is, ethinylestradiol plus dienogest or norethisterone acetate, the ratios before administration were 0.62 and 0.68, vs. 0.31 and 0.54 after 3 months, respectively. The ratio after ethinylestradiol and dienogest was significantly lower after treatment. HRT and OC in the estrogen-progestin combinations tested did not impose any negative effects on estradiol metabolism--they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.

Urinary 2/16 estrogen metabolite ratio levels in healthy women: A review of the literature

“…The methods for urine collection always involved the addition of ascorbic acid for preservation purposes, but the time of urine collection varied: a spot urine collection was used in 10 studies [4, 49, 52, 56, 57, 69, 70, 75, 77, 85, 95], while 18 studies [5, 6, 54, 55, 58-64, 68, 74, 76, 78-81, 87-94, 99] reported on overnight urine collection. The remaining studies included 12, 24, 48 or 72 urine collection protocols.…”

“…Out of the studies that addressed postmenopausal hormone usage, three did not report a significant impact on the 2/16 ratio [52, 78, 79] while another study observed significant changes in the ratio in smokers only [98]. …”

The relationship between physical activity and 2-hydroxyestrone, 16α-hydroxyestrone, and the 2/16 ratio in premenopausal women (United States)

“…Evidence exists that estrogen metabolites can be modified by human behaviors such as smoking [36][37][38], hormonal contraceptives [39,40], body fat [41][42][43], and diet [44][45][46]. Physical activity is a modifiable human behavior that may alter estrogen metabolism but research is limited.…”

Risk of breast cancer during hormone replacement therapy: mechanisms

“…We have also investigated the effects of different contraceptives because similar potential genotoxic metabolites have been described using ethinyl estradiol (78). However, it seems that proliferative mechanisms are more important, although ethinyl estradiol showed much lower effects compared to estradiol (see section on 'Different effects of estrogens on proliferation mechanisms').…”