[Neuropsychological side effects of combined hormonal contraceptives for the treatment of mild symptoms. Bioethical assessment of its adequacy]. / Efectos secundarios neuropsicológicos de los anticonceptivos hormonales combinados para el tratamiento de síntomas leves. Valoración bioética de su adecuación.

Since the beginning of the commercialization, in 1960, of combined estrogen-progestin hormonal contraceptives (CHCs), their use has become widespread for other non-contraceptive indications: dysmenorrhea, irregular cycle length, hypermenorrhea and acne, among others (Lete, 2009; Barranco, 2016). In all cases, these are mild pathologies or minor symptoms for which there are effective therapeutic alternatives. Millions of women in the world receive this treatment, which acts by inhibiting the hypothalamic-pituitary-ovarian hormonal axis (HHO Axis), the central axis and regulator of the entire sexual and reproductive physiology of women. Despite the existence of an enormous number of women subjected to this inhibition (ACHs are currently used by some 214 million women around the world, with an annual market of close to 18 billion dollars), very little research has been done on the consequences of suppressing the HHO axis. Only in recent years, and in parallel to the demonstration of the existence of functional receptors for gonadotropins at different levels in the central and peripheral nervous systems, have publications on the neuropsychological effects of HCAs begun to appear. It is also striking that, despite being the most widely used drugs and for the longest time for the treatment of functional gynecological disorders, their use is outside the technical data sheet (i.e., they are used for purposes other than those listed in the official indication approved in their technical data sheet and which appear in the package insert). Although the use of these hormonal products causes a wide variety of side effects, which have been widely studied in the medical literature, the present study proposes, after an exposition of the different aspects of the use of HCAs, a detailed review of the available literature on the neuropsychological effects due to the annulment of the HHO axis. This in order to, after a biological analysis, subsequently establish whether there is an ethical appropriateness in the use that concerns us.

Efectos secundarios neuropsicológicos de los anticonceptivos hormonales combinados para el tratamiento de síntomas leves. Valoración bioética de su adecuación / Neuropsychological side effects of combined hormonal contraceptives for the treatment of mild symptoms. Bioethical assessment of its adequacy

Desde el comienzo de la comercialización, en 1960, de los anticonceptivos hormonales combinados deestrógenos y progestágenos (ACH), se ha generalizado su utilización para otras indicaciones no anticoncep-tivas: dismenorrea, ciclos de duración irregular, hipermenorrea y acné, entre otros (Lete, 2009; Barranco,2016). En todos los casos se tratan de patologías leves o síntomas menores para los que existen alternativasterapéuticas eficaces. Millones de mujeres en el mundo reciben este tratamiento, que actúa inhibiendoel eje hormonal hipotalámico-hipofisárico-ovárico (Eje HHO), eje central y regulador de toda la fisiologíasexual y reproductiva de la mujer. Pese a la existencia de una enorme cantidad de mujeres sometidas a estainhibición (actualmente los ACH son utilizados por unos 214 millones de mujeres alrededor del mundo,con un mercado anual cercano a los 18.000 millones de dólares), se ha investigado muy poco sobre lasconsecuencias de la supresión del eje HHO. Sólo en los últimos años, y en paralelo a la demostración de laexistencia de receptores funcionales para las gonadotropinas a diferentes niveles en los sistemas nerviososcentral y periférico, comienzan a aparecer publicaciones sobre los efectos neuropsicológicos de los ACH.Llama también la atención que, pese a ser los fármacos más empleados y desde hace más tiempo para eltratamiento de las alteraciones funcionales ginecológicas, su uso esté al margen de la ficha técnica (es de-cir, se les da un uso diferente a los recogidos en la indicación oficial aprobada en su ficha técnica y que figu-ra en el prospecto). Aunque el uso de estos productos hormonales causa efectos secundarios muy variados,y ampliamente estudiados en la literatura médica, en el presente estudio se plantea, tras una exposiciónde los distintos aspectos del uso de los ACH, una revisión pormenorizada de la bibliografía disponible sobrelos efectos neuropsicológicos debidos a la anulación del eje HHO.(AU)

Since the beginning of the commercialization, in 1960, of combined estrogen-progestin hormonal con-traceptives (CHCs), their use has become widespread for other non-contraceptive indications: dysmenorrhea,irregular cycle length, hypermenorrhea and acne, among others (Lete, 2009; Barranco, 2016). In all cases, the-se are mild pathologies or minor symptoms for which there are effective therapeutic alternatives. Millions ofwomen in the world receive this treatment, which acts by inhibiting the hypothalamic-pituitary-ovarian hor-monal axis (HHO Axis), the central axis and regulator of the entire sexual and reproductive physiology of wo-men. Despite the existence of an enormous number of women subjected to this inhibition (ACHs are currentlyused by some 214 million women around the world, with an annual market of close to 18 billion dollars), verylittle research has been done on the consequences of suppressing the HHO axis. Only in recent years, and inparallel to the demonstration of the existence of functional receptors for gonadotropins at different levelsin the central and peripheral nervous systems, have publications on the neuropsychological effects of HCAsbegun to appear. It is also striking that, despite being the most widely used drugs and for the longest timefor the treatment of functional gynecological disorders, their use is outside the technical data sheet (i.e., theyare used for purposes other than those listed in the official indication approved in their technical data sheetand which appear in the package insert). Although the use of these hormonal products causes a wide varietyof side effects, which have been widely studied in the medical literature, the present study proposes, afteran exposition of the different aspects of the use of HCAs, a detailed review of the available literature on theneuropsychological effects due to the annulment of the HHO axis.(AU)

Bisphenol A and other phenols in human placenta from children with cryptorchidism or hypospadias.

Embryo-foetal exposure to low doses of endocrine disrupting chemicals (EDCs) has been related to reproductive tract diseases in experimental animals but not convincingly in human populations. The aim of this case-control study was to explore the relationship between exposure to non-persistent EDCs during pregnancy and male genital development. Exposure to bisphenol-A (BPA), benzophenones (BPs) [BP-1, BP-2, BP-3, BP-6, BP-8 and 4-hydroxybenzophenone (4-OH-BP),] and parabens (PBs) [methyl-, ethyl-, propyl- and butyl-PB] was analyzed by means of ultra-high performance liquid chromatography-tandem mass spectrometry in placenta samples from a subsample of 28 cases and 51 healthy controls nested in a cohort of newborns recruited between 2000 and 2002. The multivariable regression analyses indicated a statistically significant association between exposure to BPA and propyl-PB and the risk of malformations [adjusted odd ratio (95% CIs) in the third tertile of exposure: 7.2 (1.5-35.5) and 6.4 (1.2-35.5) for BPA and propyl-PB, respectively].

Screening of hormone-like activities in bottled waters available in Southern Spain using receptor-specific bioassays.

Bottled water consumption is a putative source of human exposure to endocrine-disrupting chemicals (EDCs). Research has been conducted on the presence of chemicals with estrogen-like activity in bottled waters and on their estrogenicity, but few data are available on the presence of hormonal activities associated with other nuclear receptors (NRs). The aim of this study was to determine the presence of endocrine activities dependent on the activation of human estrogen receptor alpha (hERa) and/or androgen receptor (hAR) in water in glass or plastic bottles sold to consumers in Southern Spain. Hormone-like activities were evaluated in 29 bottled waters using receptor-specific bioassays based on reporter gene expression in PALM cells [(anti-)androgenicity] and cell proliferation assessment in MCF-7 cells [(anti-)estrogenicity] after optimized solid phase extraction (SPE). All of the water samples analyzed showed hormonal activity. This was estrogenic in 79.3% and anti-estrogenic in 37.9% of samples and was androgenic in 27.5% and anti-androgenic in 41.3%, with mean concentrations per liter of 0.113pM 17ß-estradiol (E2) equivalent units (E2Eq), 11.01pM anti-estrogen (ICI 182780) equivalent units (ICI 182780Eq), 0.33pM methyltrienolone (R1881) equivalent units (R1881Eq), and 0.18nM procymidone equivalent units (ProcEq). Bottled water consumption contributes to EDC exposure. Hormone-like activities observed in waters from both plastic and glass bottles suggest that plastic packaging is not the sole source of contamination and that the source of the water and bottling process may play a role, among other factors. Further research is warranted on the cumulative effects of long-term exposure to low doses of EDCs.

In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors.

Bisphenols are a group of chemicals structurally similar to bisphenol-A (BPA) in current use as the primary raw material in the production of polycarbonate and epoxy resins. Some bisphenols are intended to replace BPA in several industrial applications. This is the case of bisphenol-S (BPS), which has an excellent stability at high temperature and resistance to sunlight. Studies on the endocrine properties of BPS have focused on its interaction with human estrogen receptor alpha (hERα), but information on its interaction with other nuclear receptors is scarce. The aim of this study was to investigate interactions of BPS, BPF, BPA and its halogenated derivatives, tetrachlorobisphenol A (TCBPA), and tetrabromobisphenol A (TBBPA), with human estrogen receptors (hERα and hERß), androgen receptor (hAR), and pregnane X receptor (hPXR), using a panel of in vitro bioassays based on competitive binding to nuclear receptors (NRs), reporter gene expression, and cell proliferation assessment. BPS, BPF, and BPA efficiently activated both ERs, while TCBPA behaved as weak hERα agonist. Unlike BPF and BPA, BPS was more active in the hERß versus hERα assay. BPF and BPA were full hAR antagonists (BPA>BPF), whereas BPA and BPS were weak hAR agonists. Only BPA, TCBPA, and TBBPA, were hPXR agonists (TCBPA>TBBPA>BPA). These findings provide evidence that BPA congeners and derivatives disrupt multiple NRs and may therefore interfere with the endocrine system. Hence, further research is needed to evaluate the potential endocrine-disrupting activity of putative BPA substitutes.