Endocrine Disrupting Chemicals and Pubertal Development

During the past decades, advancement in pubertal onset especially in girls has been noticed worldwide. Genetic factors and increasing prevalence of adiposity may contribute, however ubiquitous presence of endocrine disrupting chemicals (EDCs) is suspected to be involved in the trend of earlier pubertal onset. Most of known EDCs have estrogenic and/or anti-androgenic actions and few have androgenic or anti-estrogenic effects. Some studies reported earlier age at menarche after exposure to polycholorinated biphenyls (PCBs), polybrominated biphenyls, dicholordiphenyltrichloroethane, phthalate esters, while several other studies found no effect of these compounds on Tanner stages or age at menarche in girls. Limited studies reported an association of delayed puberty in boys and exposure to PCBs or the pesticide endosulfan. However, epidemiological research on the effects of EDCs on sexual maturation is hampered by many pitfalls, such as the mixture of many chemicals with different effects in environment, unidentified critical window of exposure, and limited knowledge about the time lag between exposure and effect. In this paper, we reviewed possible mode of actions of different chemical compounds, and summarized animal/human studies shown the effects of EDCs on the pubertal development.

Studies on antiestrogen compounds and their structure-activity relationships / 国际药学研究杂志

Antiestrogens have been proven to be highly effective in the treatment of estrogen receptor-dependent breast cancer. According to the mechanism, antiestrogen compounds were mainly categorized as selective estrogen receptor modulators (SERM) and pure antiestrogens, which structurally include estradiol derivatives, triphenylethylenes, benzo heterocyclic and polyphenol of natural compounds. The research advances on the antiestrogen compounds and their structure-activity relationships are reviewed.

Is there a role for antiestrogens (estrogen antagonists) in the regulation of fertility.

Estrogens secreted by the ovary during the pre/periimplantation period and/or by the blastocyst and acting locally on the endometrium are involved in the initiation of implantation. Estrogens induce a cascade of metabolic changes in the uterus and blastocyst prior to and soon after the attachment and implantation of the blastocysts. Antiestrogens either administered intraluminally into the uterus prior to implantation or washing free blastocysts with antiestrogens prior to transfer to uteri of progesterone treated hamsters leads to failure of implantation. A number of antiestrogens which inhibit fertility in the rats do not interfere with implantation in the hamster and monkey when administered post-coitally. However, Zuclomiphene administered during days 5–11 of the menstrual cycle inhibits implantation in the rhesus monkey. Antiestrogens are being evaluated in other non-human primates to confirm the above results and to determine the time in the menstrual cycle susceptible to modification and inhibition of implantation. Tamoxifen administered from days 18–30 of the cycle to mated bonnet monkeys inhibited implantation despite maintenance of high levels of circulating progesterone. Neutralization of the vitamin carrier proteins (by active immunization against these proteins) interferes with established pregnancy in the rat and perhaps in the bonnet monkey. Whether antiestrogens can reduce the levels of vitamin carrier proteins to a level which is not adequate for maintenance of early pregnancy is not clear. Compounds which show antiestrogenic and antiprogestational properties may have advantages in inhibiting implantation or disruption of early pregnancy. Critical experiments need to be carried out in non-human primates to delineate the effectiveness of antiestrogens, with particular emphasis on time, dose, duration and route of administration in inhibition of implantation. Centchroman, an antiestrogen with antiprogestational properties, has been found to provide pregnancy protection with minimal side effects. However, several concerns relating to safety in toxicological studies in monkeys and a dose which would provide acceptable rate of contraceptive efficacy without major effects on the menstrual cycle need to be clarified before considering the potential of centchroman as a possible oral contraceptive administered either post-coitally or once a week. Inhibition of implantation by administration of tamoxifen opens up new possibilities of use of antiestrogens for fertility regulation.

Hormonal modulation of reproduction–specific thiamin carrier protein in the rat.

The hormonal modulation of thiamin carrier protein in the plasma and uterine luminal secretion during the normal reproductive phases of the animal (estrous cycle and pregnancy) as well as during experimental estrogenisation was investigated in the rat using a specific and sensitive homologous radioimmunoassay procedure developed for this purpose. Following a single injection of estrogen to immature male rats, thiamin carrier protein rapidly accumulated in plasma attaining peak concentration at 48 h and declining thereafter. A 1·5- fold amplification of the inductive response was observed on secondary stimulation with the hormone. The magnitude of the response exhibited a clear dependency on the dose of the steroid hormone, whereas the time at which peak levels of thiamin carrier protein production was remained unaltered in the concentration range of the steroid tested. The inductive effect of estrogen was severely curtailed by the antiestrogens, viz., En- and Zu-clomiphene citrates, while progesterone was incapable of either modulating the estrogen-induced response or eliciting an induction by itself. Cycloheximide drastically blocked the response to estrogen. Evidence for the ability of uterus to serve as yet another independent site of thiamin carrier protein synthesis was obtained by in vitro incorporation of radioactive amino acids into immunoprecipitable thiamin carrier protein in the tissue explants of estrogenised female rats. The levels of thiamin carrier protein in uterine luminal fluid measured during estrous cycle, pregnancy and experimental estrogenisation exhibited remarkable similarity to the plasma thiamin carrier protein profiles.

Post-coital agents and menses inducing drugs.

The importance of developing of drugs which could be taken post-coitally or used once-a-month in the case of a delay in the onset of the menses is well recognized. The availability of such technology would limit exposure to fertility regulating agents to such occasions where there is coital exposure or possibility of pregnancy. Methods of post-coital contraception used so far include IUD's inserted post-coitally, estrogens, and combinations of estrogens and gestagens. These are reserved primarily for emergency situations to protect women from unwanted pregnancy resulting from rape or unprotected coitus. Levonorgestrel has shown satisfactory results in terms of contraceptive efficacy and is being further evaluated clinically. A number of problems inherent in the development of post-coital contraception are discussed. Menstrual regulation could be achieved by a number of approaches: (a) block progesterone receptors and interfere with the preparation of the endometrium for implantation; (b) luteolysis leading to decreased progesterone levels and interruption of implantation; and (c) termination of early pregnancy by prostaglandins. A number of progesterone antagonists have been evaluated. One of the compounds, RU38486 is being evaluated clinically for termination of very early pregnancy. Deglycosylated derivatives of human chorionic gonadotropin have been shown to antagonize the action of human chorionic gonadotropin and interfere with established pregnancy in rats. Appropriate methods of delivery, immunogenicity and alternate methods for production of human chorionic gonadotropin need to be considered before evaluation of the derivatives for clinical use. In vitro and in vivo models need to be developed for evaluation of the teratogenicity and embryotoxicity of post-coital and menses inducing agents. There are a number of gaps in the knowledge of the processes regulating implantation which should be investigated in rodents and in different non-human primate species.

Induction of riboflavin-carrier protein in the immature male rat by estrogen: kinetic and hormonal specificity.

The kinetics of estrogen-induced accumulation of riboflavin-carrier protein in the plasma was investigated in immature male rats using a specific and sensitive homologous radioimmunoassay procedure developed for this purpose. Following a single injection of the steroid hormone, plasma riboflavin-carrier protein levels increased markedly after an initial lag period of approximately 24 h, reaching peak levels around 96 h and declining thereafter. A 1.5 fold amplification of the inductive response was evident on secondary stimulation with the hormone. The magnitude of the response was dependent on hormonal dose, whereas the initial lag phase and the time of peak riboflavin-carrier protein induction were unaltered within the range of the steroid doses (0.1-10 mg/ kg body wt.) tested. Simultaneous administration of progesterone did not affect either the kinetics or the maximum level of the protein induced. The hormonal specificity of this induction was further adduced by the effect of administration of antiestrogens viz., En and Zu chlomiphene citrates, which effectively curtailed hormonal induction of the protein. That the induction involved de novo-protein synthesis was evident from the complete inhibition obtained upon administration of cycloheximide. Passive immunoneutralization of endogenous riboflavin-carrier protein with antiserum to the homologous protein terminated pregnancy in rats confirming the earlier results with antiserum to chicken riboflavin-carrier protein.