The Regulation of Steroid Action by Sulfation and Desulfation

Mueller, Jonathan Wolf; Gilligan, Lorna C; Idkowiak, Jan; Arlt, Wiebke; Foster, Paul A.

doi:10.1210/er.2015-1036

Cited by 334 publications

(368 citation statements)

References 419 publications

(483 reference statements)

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“…This could be due to the fact that PregS is a charged molecule, which cannot pass the plasma membrane (41). It is therefore possible that the nonpolar P4 can activate additional intracellular pathways, contributing to a more pronounced activation of CatSper.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids

Mannowetz

Miller

Lishko

2017

Proc. Natl. Acad. Sci. U.S.A.

101

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The calcium channel of sperm (CatSper) is essential for sperm hyperactivated motility and fertility. The steroid hormone progesterone activates CatSper of human sperm via binding to the serine hydrolase ABHD2. However, steroid specificity of ABHD2 has not been evaluated. Here, we explored whether steroid hormones to which human spermatozoa are exposed in the male and female genital tract influence CatSper activation via modulation of ABHD2. The results show that testosterone, estrogen, and hydrocortisone did not alter basal CatSper currents, whereas the neurosteroid pregnenolone sulfate exerted similar effects as progesterone, likely binding to the same site. However, physiological concentrations of testosterone and hydrocortisone inhibited CatSper activation by progesterone. Additionally, testosterone antagonized the effect of pregnenolone sulfate. We have also explored whether steroid-like molecules, such as the plant triterpenoids pristimerin and lupeol, affect sperm fertility. Interestingly, both compounds competed with progesterone and pregnenolone sulfate and significantly reduced CatSper activation by either steroid. Furthermore, pristimerin and lupeol considerably diminished hyperactivation of capacitated spermatozoa. These results indicate that (i) pregnenolone sulfate together with progesterone are the main steroids that activate CatSper and (ii) pristimerin and lupeol can act as contraceptive compounds by averting sperm hyperactivation, thus preventing fertilization.CatSper | steroids | lupeol | triterpenoids | pristimerin S teroid hormones control fundamental organism functions such as development, metabolism, inflammation, ion homeostasis, and reproduction. According to the conventional model, steroid hormones signal through a corresponding genomic receptor, which upon binding to a steroid hormone initiates the translocation of the hormone-receptor complex to the nucleus. There it acts as a transcription factor by altering gene expression, and such a process can take hours (1). However, there is another, much faster pathway that is initiated by steroid hormone binding to its membrane receptor on the extracellular side of the cell. The latter signaling involves second messengers and signal-transduction cascades, which often result in the activation of ion channels (1). The female hormone progesterone (P4) activates the principal calcium channel of sperm (CatSper) (2-5) and blocks the potassium channel KSper (6) via these nongenomic pathways (7). The modulation of ion channel functions by steroid hormones has been reported in the heart (8, 9), neurons (10-12), smooth muscle (13), and pancreatic beta cells (14). In marine invertebrates, the sulfated steroid cholestane acts as a chemoattractant for sea squirt sperm, which also happens via the nongenomic pathway (15). The latter represents an unconventional chemoattractant for ascidian sperm, as such factors are usually proteins or peptides and not steroids. In humans, pregnenolone sulfate (PregS), a sulfated steroid hormone similar in structure to P4, i...

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Section: Discussionmentioning

confidence: 99%

Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids

Mannowetz

Miller

Lishko

2017

Proc. Natl. Acad. Sci. U.S.A.

101

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“…The enzyme steroid sulfatase (STS), encoded by the X‐linked gene STS , cleaves sulfate groups from a variety of steroids (e.g., dehydroepiandrosterone sulfate) to convert them to precursors for a variety of estrogens and androgens that can elicit widespread and profound physiological effects (Mueller, Gilligan, Idkowiak, Arlt, & Foster, 2015). Studies in rodent models have implicated STS function in a number of aspects of cognition, including memory (Babalola et al., 2012; Johnson, Wu, Li, & Maher, 2000).…”

Section: Introductionmentioning

confidence: 99%

A genetic variant within STS previously associated with inattention in boys with attention deficit hyperactivity disorder is associated with enhanced cognition in healthy adult males

et al. 2017

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IntroductionThe enzyme steroid sulfatase (STS) converts sulfated steroids to their non‐sulfated forms. Deficiency for this enzyme is associated with inattention but preserved response control. The polymorphism rs17268988 within the X‐linked STS gene is associated with inattentive, but not other, symptoms in boys with attention deficit hyperactivity disorder (ADHD).MethodsWe initially tested whether rs17268988 genotype was associated with attention, response control, and underlying aspects of cognition, using questionnaires and neuropsychological tasks, in two independent cohorts of healthy adult males. In an additional analysis based upon existing data, the performance of mice with genetic or pharmacological manipulations of the STS axis under attentionally demanding conditions was investigated.ResultsG‐allele carriers at rs17268988 exhibited reduced reaction time, enhanced attention, and reduced reaction time variability relative to C‐allele carriers. Mice with genetic or pharmacological manipulations of the STS axis were shown to have perturbed reaction time variability.DiscussionOur findings provide additional support for an association between rs17268988 genotype and attention, which may be partially mediated by reaction time variability; they also indicate that, in contrast to the situation in boys with ADHD, in healthy men, the G‐allele at rs17268988 is associated with enhanced cognition. As reaction time variability is a predictor of well‐being, rs17268988 genotype may represent a biomarker for long‐term health.

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“…STS is widely expressed in almost all peripheral tissues and is responsible for hydrolysing sulphate moieties off of circulating sulphate-conjugated steroids in order to make them biologically active (Mueller et al 2015). Oestrone sulphate (E 1 S) is the most abundant circulating oestrogen in adult humans (Muir et al 2004) with plasma levels between 2 and 4 nmol/L in men (Mueller et al 2015), and while oestradiol sulphate also exists, plasma levels are very low.…”

Section: :6mentioning

confidence: 99%

In touch with your feminine side: how oestrogen metabolism impacts prostate cancer

Rahman

Hofland

Foster

2016

Endocrine-Related Cancer

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Prostate cancer is the primary cancer in males, with increasing global incidence rates making this malignancy a significant healthcare burden. Androgens not only promote normal prostate maturity but also influence the development and progression of prostate cancer. Intriguingly, evidence now suggests endogenous and exogenous oestrogens, in the form of phytoestrogens, may be equally as relevant as androgens in prostate cancer growth. The prostate gland has the molecular mechanisms, catalysed by steroid sulphatase (STS), to unconjugate and utilise circulating oestrogens. Furthermore, prostate tissue also expresses enzymes essential for local oestrogen metabolism, including aromatase (CYP19A1) and 3β- and 17β-hydroxysteroid dehydrogenases. Increased expression of these enzymes in malignant prostate tissue compared with normal prostate indicates that oestrogen synthesis is favoured in malignancy and thus may influence tumour progression. In contrast to previous reviews, here we comprehensively explore the epidemiological and scientific evidence on how oestrogens impact prostate cancer, particularly focusing on pre-receptor oestrogen metabolism and subsequent molecular action. We analyse how molecular mechanisms and metabolic pathways involved in androgen and oestrogen synthesis intertwine to alter prostate tissue. Furthermore, we speculate on whether oestrogen receptor status in the prostate affects progression of this malignancy.

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The Regulation of Steroid Action by Sulfation and Desulfation

Cited by 334 publications

References 419 publications

Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids

Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids

A genetic variant within STS previously associated with inattention in boys with attention deficit hyperactivity disorder is associated with enhanced cognition in healthy adult males

In touch with your feminine side: how oestrogen metabolism impacts prostate cancer

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