Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes

Drug efficacy is dependent on the pharmacokinetics and pharmacodynamics of therapeutic agents. Tight junctions, detoxification enzymes, and drug transporters, due to their localization on epithelial barriers, modulate the absorption, distribution, and the elimination of a drug. The epithelial barriers which control the pharmacokinetic processes are sex steroid hormone targets, and in this way, sex hormones may also control the drug transport across these barriers. Thus, sex steroids contribute to sex differences in drug resistance and have a relevant impact on the sex-related efficacy of many therapeutic drugs. As a consequence, for the further development and optimization of therapeutic strategies, the sex of the individuals must be taken into consideration. Here, we gather and discuss the evidence about the regulation of ATP-binding cassette transporters by sex steroids, and we also describe the signaling pathways by which sex steroids modulate ATP-binding cassette transporters expression, with a focus in the most important ATP-binding cassette transporters involved in multidrug resistance. (AU)

Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes.

Drug efficacy is dependent on the pharmacokinetics and pharmacodynamics of therapeutic agents. Tight junctions, detoxification enzymes, and drug transporters, due to their localization on epithelial barriers, modulate the absorption, distribution, and the elimination of a drug. The epithelial barriers which control the pharmacokinetic processes are sex steroid hormone targets, and in this way, sex hormones may also control the drug transport across these barriers. Thus, sex steroids contribute to sex differences in drug resistance and have a relevant impact on the sex-related efficacy of many therapeutic drugs. As a consequence, for the further development and optimization of therapeutic strategies, the sex of the individuals must be taken into consideration. Here, we gather and discuss the evidence about the regulation of ATP-binding cassette transporters by sex steroids, and we also describe the signaling pathways by which sex steroids modulate ATP-binding cassette transporters expression, with a focus in the most important ATP-binding cassette transporters involved in multidrug resistance.

Estrogen receptors alpha and beta in human testis: both isoforms are expressed.

Currently, clinical and experimental evidence point to an essential role of estrogens and estrogen receptors in male fertility. The expression of estrogen receptor alpha (ERalpha) and beta (ERbeta) in human testis has been described. However, some studies were unable to detect ERalpha, while others report the expression of both isoforms, with ERbeta presenting a wide distribution within somatic and germinal testicular cells. This has suggested that estrogens may exert their testicular effects exclusively through ERbeta. The present work aims to study the expression of ERalpha and ERbeta in testicular biopsies of men with conserved and disrupted spermatogenesis, in order to better clarify the positive cell populations. Human testicular tissue was obtained from 10 men undergoing testicular biopsy for infertility relief due to azoospermia: two patients had secondary obstructive azoospermia with conserved spermatogenesis, five had Sertoli cell-only syndrome, two had hypospermatogenesis and one had meiotic arrest. Reverse-transcription polymerase chain reaction (RT-PCR) allowed the detection of both ERalpha and ERbeta mRNAs in all samples. Immunohistochemistry revealed that ERalpha was present in Leydig cells, Sertoli cells, spermatogonia, spermatocytes, round spermatids and elongated spermatids/spermatozoa, while ERbeta was present in the same cell types except spermatogonia and Sertoli cells. This study demonstrates ERalpha mRNA expression in human testis and describes its localization in somatic and germ cell subtypes. These findings suggest that both ER isoforms are involved in the control of testicular function.