Estradiol levels

The effects of raloxifene in premenopausal women have been analyzed in subjects with normal ovarian function treated with high doses (100 to 400 mg daily) at either different time points of their menstrual cycle or continuously for 4 weeks (Baker et al. 1998). Raloxifene did not prevent ovulation, nor did it alter the length of the menstrual cycle or the day of the LH surge. However, it did stimulate FSH secretion, increase serum estradiol levels, and decrease serum PRL. These results are also similar to those reported for premenopausal women taking tamoxifen (Jordan et al. 1991) and are indicative of some antiestrogenic action at either the hypothalamic and/or pituitary level. 

Reindollar R, Koltun W, Parsons A, Rosen A, Siddhanti S, Plouffe Jr L (2002) Effects of oral raloxifene on serum estradiol levels and other markers of estrogenicity. Fertil Steril 78 469-472... 

In those with serum estradiol concentrations of 5-10 pmol/L, invasive breast cancer incidence was reduced by 67% (HR = 0.33, 95% Cl = 0.13-0.84 ARR = 40 cases per 10,000 woman-years) in the raloxifene group compared to those receiving placebo. In women with serum estradiol levels < 5 pmol/L, the 48% reduction in invasive breast cancer incidence for the raloxifene group compared to placebo was not significant (HR = 0.52, 95% Cl = 0.26-1.06 ARR =11 cases per 10,000 woman-years). However, the interaction test showed that the magnitude of reduction in breast cancer incidence with raloxifene was independent of estradiol level (interaction p = 0.317). 

Fig. 10.12. Effect of raloxifene on the risk of invasive breast cancer at different serum estradiol levels evaluated in two different studies. Elaborated from Lippman et al. (2001) and Cummings et al. (2002a)...

Cummings SR, Duong T, Kenyon E et al. (2002a) Serum estradiol level and risk of breast cancer during treatment with raloxifene. J Am Med Assoc 287 216-220... 

Cummings SR (2002b) Measurement of serum estradiol levels in postmenopausal women. J Am Med Assoc 288 451... 

A possible explanation for these results may be twofold. First, the raloxifene doses were too low to reduce or reverse the proliferative effect of serum estradiol in normal ovulatory women. In fact, in postmenopausal women serum estradiol levels are about tenfold lower in comparison with normally cycled premenopausal women. Second, it is possible that in postmenopausal women ERs have a different intratumoral pattern in terms of concentration, expression, and affinity in comparison with premenopausal women. 

Recently, a Japanese research group published preclinical safety and efficacy data of an oral antiestrogen (TZE-5323) (Saito et al. 2003). This drug has been shown to have a strong affinity for human ERa and ER/i and a dose-dependent capacity to inhibit estradiol-stimulated transcriptional activation (Saito et al. 2003). In the experimental endometriosis model in rats, TZE-5323 dose-dependently reduced the volume of the endometrial implant with an effectiveness similar to that of danazol and leuprorelin acetate without causing significant changes in bone mineral density and in serum estradiol levels (Saito et al. 2003). 

Pryce, C. R., Abbott, D. H., Hodges, J. K., and Martin, R. D. 1988. Maternal behavior is related to prepartum urinary estradiol levels in red-bellied tamarin monkeys. Physiology and Behavior 44 717-726. 

Gonadotropins are used to treat infertility in women with potentially functional ovaries who have not responded to other treatments. The therapy is designed to simulate the normal menstrual cycle as far as is practical. A common protocol is daily injections of menotropins for 9 to 12 days, until estradiol levels are equal to that in a normal woman, followed by a single dose of hCG to induce ovulation. Two problems with this treatment are risks of ovarian hyperstimulation and of multiple births. Ovarian hyperstimulation is characterized by sudden ovarian enlargement associated with an increase in vascular permeability and rapid accumulation of fluid in peritoneal, pleural, and pericardial cavities. To prevent such occurrences, ovarian development is monitored during treatment by ultrasound techniques and by measurements of serum levels of estradiol. 

E. Therapeutic response In anovulatory women, the goal of therapy is adequate follicular development as determined by ultrasound in combination with measurement of serum estradiol levels. In men, the aim of treatment is maintenance of serum testosterone levels within the normal range. 

E. Therapeutic response Follicle maturation during follitropin beta therapy is best monitored by daily ultrasonography and daily measurement of serum and/or urine estradiol levels. Ovulation may be clinically confirmed by an increase in serum progesterone as well as an elevation in basal body temperature. 

Frezza, E.E., Gerunda, G.E., Farinati, F., DeMaria, N., Galligioni, A., Plebani, F., Giacomin, A Van Thiel, D.H. (1994) CCl4-induced liver cirrhosis and hepatocellular carcinoma in rats relation to plasma zinc, copper and estradiol levels. Hepato-Gastroenterology, 41, 367-369... 

Sinofsky FE, Pasquale SA. The effect of fluconazole on circulating ethinyl estradiol levels in women taking oral contraceptives. Am J Obstet Gynecol 1998 178(2) 300-4. 

Increased clearance of steroid hormones due to induction of hepatic biotransformation enzymes following chemical exposure often has been cited as a possible mechanism by which toxicants could lower circulating testosterone or 17/3-estradiol levels. While enhanced clearance of sex steroids has been demonstrated following chemical exposure and induction of hepatic biotransformation enzymes, elegant feedback control mechanisms tend to ensure that more hormone is produced and homeostasis is maintained (Figure 17.2). Enhanced clearance of sex steroids can contribute to endocrine disruption if the toxicity also results in impaired hormone synthesis (i.e., gonadal toxicity or interference with the feedback control of hormone synthesis). 2,3,7,8-Tetrachlorodibenzodioxin appears to lower circulating sex steroid levels via this dual effect. 

Gonadorelin is administered intravenously, 5 pg every 90 minutes from a portable pump. The woman is followed carefully with serum estradiol levels, and an ovarian ultrasound examination is done weekly before refilling the GnRH pump. When an ovarian follicle reaches 14 mm in diameter, ovulation is induced with hCG, 5000 units subcutaneously, and the luteal phase is maintained with hCG, 1500 units every 3 days for 12 days. 

In hypothalamic hypogonadism and for in vitro fertilization, one or two ampules are administered daily for 5-12 days until evidence of adequate follicular maturation is present. Serum estradiol levels should be measured and a cervical examination performed every 1 or 2 days. When appropriate follicular maturation has occurred, hMG or FSH is discontinued the following day, hCG (5000-10,000 IU) is administered intramuscularly to induce ovulation. 

Patients with constitutional delay in onset of puberty can be distinguished from those with hypogonadotropic hypogonadism using repeated hCG stimulation. Serum testosterone and estradiol levels rise in the former but not in the latter group. 

Few studies have investigated the reproductive toxicity of DEHP in female animals. When female mice were exposed to a dietary dose of 420 mg/kg/day DEHP for 105 days and mated with unexposed males, combined weights of the ovaries, oviducts, and uterus were reduced, and no litters were produced. When female mice exposed to 14 or 140 mg DEHP/kg/day were mated with males given these same doses, there was a dose-related decline in the number of litters, live pups per litter, and live pup weight. Short-term gavage exposure to a very high level of DEHP (2,000 mg/kg/day), particularly with respect to possible human exposure, had clear effects on estradiol synthesis, manifested as decreased serum estradiol levels and anovulatory cycles and polycystic ovaries, in female rats. These data indicate that oral exposure to DEHP can affect reproductive processes in female rodents. 

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