Estradiol exerts alterations in sexual function and fertility in human males

The hypothalamic-pituitary-gonadal (HPG) axis represents a complex interplay in which male reproductive and sexual functions are regulated. The role of estrogen, once relegated to being that of a minor player, has had its importance resurrected by a recent research.

With regards to male fertility, Clomiphene citrate and tamoxifen are selective estrogen receptor modulators and the medications most frequently used in the management of male fertility and hypogonadism. Usage of Clomiphene results in a concomitant rise in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at the level of the pituitary, resulting in an increase in intratesticular and serum testosterone levels and theoretically creating a more favorable environment for sperm production within the testis. Aromatase inhibitors, such as Arimidex, are primarily used in patients with a testosterone to estradiol ratio <10:1 to increase testosterone production and spermatogenesis. Targeting estradiol levels has also been shown to have clinical value when optimizing sperm retrieval rates in men with nonobstructive azoospermia.1

Endogenous and exogenous estrogens may limit the efficacy of Clomiphene treatment by both direct pituitary inhibition and at the level of the testis. Estrogenic excess from the peripheral aromatization of adipose tissue can also lead to a direct inhibitory effect of pituitary function and, thus, impaired spermatogenesis.

Clomiphene is a mixture of two diastereoisomers with zuclomiphene, the cis isomer, exhibiting a longer serum half-life and demonstrating the properties of estrogen receptor agonism. Enclomiphene, the trans isomer, functions primarily as an estrogen antagonist. Research is currently being conducted on the latter's effects on sperm and testosterone production.2

The role of estrogen in sexual function has similarly been underappreciated. As Schulster et al.3 acknowledge in their chapter, estradiol significantly impacts early sexual development, modulates adult male sexual behavior, influences libido, and regulates mood. A recent study by Finkelstein et al.4 found that administration of testosterone concurrently with aromatase inhibitors markedly impaired sexual functioning. Similarly, Ramasamy et al.5 posed a compelling argument by demonstrating that in men with serum testosterone <300 ng dl⁻¹, libido was significantly improved when estradiol levels were >5 ng dl⁻¹ It thus appears that both estrogen and testosterone are necessary for libido in hypogonadal men. The role of estradiol in erectile function is less clear.

In some situations, it is possible to identify men with infertility and hypogonadism attributable to hyperestrogenism. In those situations, once an estrogen-secreting tumor has been excluded, the most appropriate treatment of infertility resultant from estrogen excess can be enigmatic.6 In men with obesity, estrogenic excess is commonly identifiable with concurrent infertility. While options such as the aromatase inhibitors anastrozole, aromasin, and letrozole exist; further research to elucidate the optimal therapy in these men needs to be conducted.