Martin Hill

Steroid metabolome in fetal and maternal body fluids in human late pregnancy

Despite the extensive research during the last six decades the fundamental questions concerning the role of steroids in the initiation of human parturition and origin and function of some steroids in pregnancy were not definitely answered. Based on steroid metabolomic data found in the literature and our so far unpublished results, we attempted to bring new insights concerning the role of steroids in the sustaining and termination of human pregnancy, and predictive value of these substances for estimation of term. We also aimed to explain enigmas concerning the biosynthesis of progesterone and its bioactive catabolites considering the conjunctions between placental production of CRH, synthesis of bioactive steroids produced by fetal adrenal, localization of placental oxidoreductases and sustaining of human pregnancy. Evaluation of data available in the literature, including our recent findings as well as our new unpublished data indicates increasing progesterone synthesis and its concurrently increasing catabolism with approaching parturition, confirms declining production of pregnancy sustaining 5β-pregnane steroids providing uterine quiescence in late pregnancy, increased sulfation of further neuroinhibiting and pregnancy sustaining steroids. In contrast to the established concept considering LDL cholesterol as the primary substrate for progesterone synthesis in pregnancy, our data demonstrates the functioning of alternative mechanism for progesterone synthesis, which is based on the utilization of fetal pregnenolone sulfate for progesterone production in placenta. Close relationships were found between localization of placental oxidoreductases and consistently higher levels of sex hormones, neuroactive steroids and their metabolites in the oxidized form in the fetus and in the reduced form in the maternal compartment.

Effects of valproate and carbamazepine monotherapy on neuroactive steroids, their precursors and metabolites in adult men with epilepsy

Only limited data is available concerning the role of unconjugated Δ(5) C19-steroids and almost no data exists regarding the neuroactive C21 and C19 3α-hydroxy-5α/β-metabolites in men with epilepsy. To evaluate the alterations in serum neuroactive steroids and related substances in adult men with epilepsy on valproate and carbamazepine monotherapy, we have measured 26 unconjugated steroids, 18 steroid polar conjugates, gonadotropins and sex hormone binding globulin (SHBG) in 6 and 11 patients on valproate and carbamazepine monotherapy, respectively, and in 19 healthy adult men, using the GC-MS and immunoassays. Decreased testosterone, free androgen index, free testosterone, androstenediol, 5α-androstane-3α,17β-diol (androstanediol), androsterone, epiandrosterone, DHEA, 7β-hydroxy-DHEA, and DHEAS levels were associated with epilepsy per se. Valproate (VPA) therapy increased 5α-dihydrotestosterone, androsterone, epiandrosterone, DHEA, DHEAS, and 7β-hydroxy-DHEA levels. Decrease in pregnenolone and 17-hydroxypregnenolone were associated with epilepsy with no effect of antiepileptic drugs (AEDs). Alternatively, the increase in progesterone levels was linked to epilepsy and VPA further increased progesterone levels. Reduced steroid 20α-hydroxy-metabolites and cortisol were connected with epilepsy without an effect of AEDs. Carbamazepine induced only slight decrease in isopregnanolone, 5α,20α-tetrahydroprogesterone, and androstanediol levels.

The steroid metabolome in lamotrigine-treated women with epilepsy.

BACKGROUNDnEpilepsy in women may be associated with reproductive disorders and alterations in serum steroid levels. Some steroids can be induced by epilepsy and/or treatment with antiepileptic drugs; however, there are still limited data available concerning this effect on the levels of other neuroactive steroid metabolites such as 3a-hydroxy-5a/b-reduced androstanes.nnnAIMnTo evaluate steroid alterations in women with epilepsy (WWE) on lamotrigine monotherapy.nnnSUBJECTS AND METHODSnEleven WWE and 11 age-matched healthy women underwent blood sampling in both phases of their menstrual cycles (MCs). The steroid metabolome, which included 30 unconjugated steroids, 17 steroid polar conjugates, gonadotropins, and sex hormone-binding globulin (SHBG), was measured using gas chromatography-mass spectrometry (GC-MS) and radioimmunoassay (RIA).nnnRESULTSnWWE had lower cortisol levels (status p<0.001), but elevated levels of unconjugated 17-hydroxypregnenolone (status p<0.001). Progesterone was higher in the follicular menstrual phase (FP) in WWE than in the controls (status×menstrual phase p<0.05, Bonferroni multiple comparisons p<0.05), whereas 17-hydroxyprogesterone was higher in WWE in both menstrual phases (status p<0.001). The steroid conjugates were mostly elevated in WWE. The levels of 5α/β-reduced androstanes in WWE that were significantly higher than the controls were etiocholanolone (status p<0.001), 5α-androstane-3α,17β-diol (status p<0.001), and the 5α/β-reduced androstane polar conjugates (status p<0.001).nnnCONCLUSIONSnWWE showed a trend toward higher circulating 3α-hydroxy-5α/β-reduced androstanes, increased activity of 17α-hydroxylase/17,20 lyase in the Δ(5)-steroid metabolic pathway, and increased levels of the steroid polar conjugates.

The role of steroids in the development of post-partum mental disorders.

BACKGROUNDnUnfavorable post-partum changes to mental well-being affect more than half of all women, and are a risk to the health of both mother and baby. Their effects place strains on health and social systems. Currently, no generally accepted theory exists of the causes and mechanisms of post-partum mental disorders.nnnMETHODSnLiterature search up to 2012, using PubMed and search words: neuroactive steroids, post-partum mental disorders, depression, corticotropin-releasing hormone and estrogens.nnnRESULTSnThere are several theories for post-partum depression. One is that autoimmune diseases are involved. Others revolve around genes responsible or that lead to increased disposition to the disorder. It is likely however that the process is associated with the separation of the placenta and the fetal zone of fetal adrenal gland, the main sources of corticotropin-releasing hormone and sexual and neuroactive steroids during pregnancy, and the ability of the receptor system to adapt to these changes. The central nervous system is able to produce neurosteroids, but the drop in levels of peripheral steroids likely leads to a sudden deficit in neuroinhibitory steroids modulating ionotropic receptors in the brain.nnnCONCLUSIONSnPost-partum depression is a multifactorial disease with unknown etiology. It is probably associated with sudden changes in the production of hormones influencing the nervous system, and on the other hand the ability of the receptor system to adapt to these changes. When the relative changes in concentrations of hormones, rather than their absolute levels, is likely more important.

Profiling of neuroactive steroids, their precursors and metabolites in patients suffering from multiple sclerosis

We have followed the neuroprotective, GABAergic glycinergic, glutamatergic acetylcholinergic and purinergic NAS, their precursors and metabolites and their conjugates (64 steroids) in the circulation and cerebrospinal fluid of 13 female patients36 years old median age and 8 sex age matched healthy controls (both in the follicular menstrual phase) with the use of gas chromatography – mass spectrometry. Conclusion

Hyperparathyroidism in Hemodialyzed Patients – Relation to Melatonin and Reproductive Hormones Before and After Parathyroidectomy

Currently there is considerable interest generated about the interaction of parathyroid glands, possible role of melatonin and reproductive hormones on bone metabolism. In hemodialyzed (HD) patients with hyperparathyroidism (HPT) the melatonin concentrations are affected, but still not well studied. It has been also pointed out that the removal of the pineal gland or administration of its extracts produces alterations in the morphology and hormone secretion of the parathyroid glands (Kiss et al., 1969; Shoumura et al., 1992). On the other hand, parathyroidectomy (PTX) leads to sleep disturbances (Chou et al., 2005).

Physiological Relevance of Pregnanolone Isomers and Their Polar Conjugates with Respect to the Gender, Menstrual Cycle and Pregnancy

5Ǐ/ǐ-Reduced progesterone metabolites (PM) including pregnanolone isomers (PI) and their polar conjugates (PIC), are efficient neuromodulators operating in a number of physiological and pathological processes including psychiatric diseases or problems connected with pregnancy, parturition and postpartum period. The substances mostly belong to the group of neuroactive steroids. The neuroactive steroids (including PI) originating directly in the central and peripheral nervous system are called neurosteroids. They have a wide variety of functions. Some neuroactive steroids are able to easily pass through the blood-brain barrier (Bixo, Andersson, Winblad, Purdy, & Backstrom, 1997; Kancheva, et al., 2010; M. D. Wang, Wahlstrom, & Backstrom, 1997). Disorders in their biosynthesis or malfunctions in interactions with the target sites can be the cause of many pathologies, including psychiatric illnesses (Backstrom, et al., 2003; Backstrom, Carstensen, & Sodergard, 1976). In contrast with the most common steroid hormones acting, neuroactive steroids largely affect non-genomic mechanisms and influence nerve excitability in both directions. Some neuroactive steroids, such as allopregnanolone and its derivates, also show neuroprotective effects (Ciriza, Azcoitia, & Garcia-Segura, 2004; Morfin & Starka, 2001; Shi, Schulze, & Lardy, 2000). The enzymes involved in the neurosteroidogenesis can be classified in two main groups: the cytochrome P450 and the non-P450 group. Experiments proved the direct biosynthesis of steroids in the brain independent of the periphery (Corpechot, Leclerc, Baulieu, & Brazeau, 1985; Corpechot, Robel, Axelson, Sjovall, & Baulieu, 1981). Three years later, Harrison and Simmonds published their work on the anesthetic effect of the synthetic pregnane steroid ganaxalone through modulation of the stimulation of the Ǒ-aminobutyric acid receptor (GABA-r) (Harrison & Simmonds, 1984). The following year Majewska and coworkers published the first study on the modulation effect of endogenous steroids on GABA-r, and thereby initiated an intense research effort focused on the mechanisms of action of neuroactive steroids (Majewska, Bisserbe, & Eskay, 1985).