What role of estrogens in ovarian stimulation

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Estrogens and progesterone represent the key ovarian hormones produced by the developing ovulatory follicle. Serum concentrations start to rise from the mid-follicular phase onwards, coinciding with the development of the dominant follicle. Androgens are converted into estrogens by aromatase activity of the granulosa cells and secreted into the follicular fluid compartment. Their significance for oocyte maturation and fertilizing potential remains unknown. Paradoxically, serum estrogen levels are within the normal range in the majority of patients presenting with cycle abnormalities due to ovarian dysfunction. Similarly, the distribution of estradiol (E 2) and follicle-stimulating hormone (FSH) levels within the normal range is comparable between normo-ovulatory controls and normogonadotropic anovulatory women. Moreover, E 2 levels are only moderately correlated with luteïnizing hormone (LH), testosterone (T), androstenedione (A), sex hormone binding globulin (SHBG), the free androgen index (FAI) and finally ovarian volume as measured by ultrasound. No correlations could be found between E 2 and age, body weight and cycle history and FSH. Androgen concentrations and cycle history – but not E 2 – were the most prominent predictors of ovarian response tot the conventional ovulation induction. Anti-estrogenic compounds like clomiphene citrate and tamoxifen have remained the first-line treatment of choice for anovulation. Certainly, CC and to a lesser extent tamoxifen have demonstrated to exhibit undesired anti-estrogenic properties at the uterine level however. However, large follow-up studies demonstrate cumulative ovulation rates around 75%, and the overall pregnancy rates of around 50%. Aromatase inhibitors, another way to interfere with estrogen feedback, represent a feasible option. This claim should, however, be substantiated by further sufficiently powered, controlled studies, and the possibility of embryo toxicity remains a major concern. In retrospect, CC and tamoxifen represent the first generation of selective estrogen receptor modulators (SERMs), and many new compounds have recently been introduced into the clinic or are currently under investigation. The major focuses of these compounds are bone density, the cardiovascular system and breast cancer. No studies have been reported in the area of ovarian stimulation.