Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Umeå universitet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Dissertation (Ph.D.)--University of Toledo, 2008. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Bibliography: p. 62-66, p.145-147, p.193-199, p. 214-245.

Endocrine disrupting compounds (EDC) are environmental contaminants that disrupt reproduction, development and behaviour in aquatic organisms. A thorough evaluation of the impacts of EDCs on aquatic organisms is currently limited by a lack of robust biomarkers in small model fish, particularly for assessing EDCs with (anti-)androgenic activity. Male sticklebacks build nests using spiggin, an androgen-responsive glycoprotein, which can be used to assess (anti-)androgenic exposure. EDC assessment in the field using threespine stickleback and the spiggin biomarker is limited to coastal and estuarine environments. However, their freshwater relative, brook stickleback (Culaea inconstans), also possess spiggin and their widespread distribution suggests that they may have applications as a bioindicator of EDCs in freshwater systems. Therefore, the overall objective of this thesis was to determine if brook stickleback are a suitable bioindicator species for EDCs by evaluating their response and sensitivity to estrogenic and (anti-)androgenic chemicals. Basal transcript levels of spiggin in kidney and vitellogenin in liver were first measured in wild-caught brook stickleback using qPCR and found to be differentially expressed in males and females. Brook stickleback were then exposed to two model compounds, 17α-ethinylestradiol (EE2) and 17α-methyltestosterone (MT), at 1, 10 and 100 ng/L for 21 days (sampled at 7 and 21 days) via static-renewal to determine the responsiveness of these transcripts to exogenous hormones. The effect of hormone exposure on condition factor, organosomatic indices and histopathology of kidneys was also measured. Exposure to MT and EE2 significantly induced spiggin and vitellogenin transcripts in female kidneys and male livers, respectively. Exposure to EE2 also significantly increased the hepatosomatic index in females after 7 days and in both sexes after 21 days whereas the gonadosomatic index was reduced in females after 21 days. An increase in kidney epithelium cell height was also observed in MT-exposed females and males after 7 days. These results mirror those of threespine stickleback and suggest that brook stickleback are responsive to androgenic and estrogenic chemical exposure and more specifically, possess quantifiable and sensitive biomarkers for exposure to compounds with androgenic activity. In a third experiment, female fish were co-exposed to MT at 500 ng/L and an anti-androgen (flutamide; FL) at 25, 150 and 250 µg/L for 14 days (sampled at 4 and 14 days) to validate this bioassay for the evaluation of anti-androgens using the same endpoints as in the previous two experiments. In females, exposure to MT increased spiggin transcript levels and nephrosomatic index (NSI) but co-exposure to FL did not result in a significant suppression of these endpoints because of high inter-individual variability. In males, exposure to MT increased NSI and co-exposure to FL resulted in a reduction in this endpoint, illustrating anti-androgenic effects. Although the response of brook stickleback to hormone exposure was endpoint-specific and was at times lower than other small model fish species, the ability to simultaneously assess estrogenic and (anti-)androgenic chemical exposure in a single fish using quantitative endpoints is an advantage exclusively held by members of the stickleback family. The results of this thesis suggest that brook stickleback hold promise as an additional small fish model for the evaluation of EDCs, with potential application in EDC biomonitoring in the freshwaters of North America.

Individuals who identify themselves as transgender have gender identities that do not match their anatomical sex. Females who identify as male, also known as female-to-male transgender (FTM), may opt to undergo hormonal and surgical treatment in order to transition to the male phenotype, including high-dose testosterone treatment to develop male secondary sexual characteristics and surgical procedures. Currently, the recommendation is for the patient to have a hysterectomy within five years of initiating testosterone therapy to decrease the risk of developing endometrial cancer. However, long-term testosterone treatment has not been proven to cause an increased risk of endometrial cancer. With the use of gene expression and immunohistochemical studies, this study aimed to show no upregulation of genes associated with proliferation (Ki-67) and endometrial cancer (ZIC2) in endometrial tissue from FTM individuals treated with long-term testosterone compared to endometrial tissue from postmenopausal women, premenopausal women with benign endometrium, and women with endometrial cancer. Our findings showed that Ki-67 and ZIC2 expression in the FTM samples was significantly lower than in the endometrial cancer samples. Our findings call into question the concept that long-term testosterone treatment causes neoplastic changes in endometrial tissue and the need for routine hysterectomy in these patients. / 2018-07-11T00:00:00Z

abstract: After natural menopause in women, androstenedione becomes the primary hormone secreted by the residual follicle deplete ovaries. Two independent studies, in rodents that had undergone ovarian follicular depletion, found that higher serum androstenedione levels correlated with increased working memory errors. This led to the hypothesis that androstenedione impairs memory. The current study directly tested this hypothesis, examining the cognitive effects of androstenedione administration in a rodent model. Middle-aged ovariectomized rats received vehicle or one of two doses of androstenedione (4 or 8 mg/kg daily). Rats were tested on a spatial working and reference memory maze battery including the water radial arm maze, Morris maze, and delay-match-to-sample task. Results showed that androstenedione at the highest dose impaired reference memory and working memory, including ability to maintain performance as memory demand was elevated. The latter was true for both high temporal demand memory retention of one item of spatial information, as well as the ability to handle multiple items of spatial working memory information. Glutamic acid decarboxylase (GAD) levels were measured in multiple brain regions to determine whether the gamma-aminobutyric acid (GABA) system mediates androstenedione's cognitive impairments. Results showed that higher entorhinal cortex GAD levels were correlated with poorer Morris maze performance, regardless of androstenedione treatment. These findings suggest that androstenedione, the main hormone produced by the follicle deplete ovary, is detrimental to spatial learning, reference memory, and working memory, and that spatial reference memory performance might be related to the GABAergic system. / Dissertation/Thesis / M.A. Psychology 2012

As the most frequently diagnosed cancer in North American men, prostate cancer can progress to the androgen independent stage after initial response to androgen ablation therapy. The molecular mechanisms involved in the hormonal progression of prostate cancer are not completely understood. Here, we analyze changes in the transcriptome of prostate cancer cells at different stages of progression to reveal potential mechanisms. Applying Affymetrix GeneChip technology, we identified the transcriptomes in response to stimulation of androgen and PKA pathways in human prostate cancer cells. In addition to PSA, other common target genes were identified. Genes differentially expressed in response to androgen and stimulation of the PKA pathway in vitro were also differentially expressed during hormonal progression in vivo. Upon androgen stimulation, androgen receptor binds to a functional androgen response element within the promoter region of SESN1, a p53 targeted gene, and represses its expression. The expression of SESN1 was induced by castration in LNCaP xenografts, but the expression was eventually suppressed again in the androgen independent stage of prostate cancer. Knockdown of SESN1 promoted the proliferation of prostate cancer cells. Expression patterns of androgen-regulated genes in androgen independent tumours were revealed to be more similar to that from before castration than to the tumors under androgen ablation. The β-catenin, a potent coactivator of the androgen receptor, and Wnt pathway was deregulated in androgen-independent tumours. There was increased nuclear colocalization and interaction of androgen receptor and β-catenin with hormonal progression of prostate cancer. This study provides insight into hormonal effects on prostate cancer and possible pathways involved in the development of androgen independent disease, as well as potential therapeutic targets. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

The mechanism by which prostate cancer progresses from androgen dependence (AD) to androgen independence/castration resistance (AI/CR) is currently a major focus of prostate cancer-related research. Prostate cancers that progress to a state of AI/CR are typically resistant to most standard types of treatments. Due to its primary role in driving normal prostate cell growth and proliferation, the androgen receptor (AR) is believed to play a key role in progression. Coregulators, or any proteins which may either enhance or abrogate AR activity, are considered to be one of the potential mechanisms by which AR function may become impaired. Cyclin G-associated kinase (GAK) was initially identified as a potential coregulator of AR in a Tup 1 repressed transactivation system. A LNCaP cDNA library was screened for proteins which interacted with the NH2-terminus of AR. GAK was isolated from three independent library clones using two different AR baits (AR 1-549 and AR 1-646). This interaction was confirmed via GST pulldown and coimmunoprecipitation experiments, and preliminary luciferase assays suggested that GAK activates AR in a hormone dependent manner. In this study, my objectives were to validate GAK’s role as a coregulator of AR and to determine if overexpressing GAK affects progression to AI. In vitro luciferase assays whereby GAK was either overexpressed or knocked down in both LNCaP and PC3 cells did not significantly affect AR activity. Xenograft experiments utilizing a doxycycline (DOX) inducible lentiviral LNCaP-GAK overexpressing stable cell line demonstrated that while GAK may not play a significant role in modulating AR activity, it may adopt a more subtle role enhancing tumour take and tumour volume growth rate in vivo. While these results could not confirm GAK to be a direct coregulator of AR, it is entirely possible that GAK may influence prostate cancer progression, albeit indirectly. Recent publications report a growing amount of evidence suggesting GAK’s involvement in the critical cellular process of clathrin coated vesicle endocytosis, the dysregulation of which could potentially indirectly affect AR regulated genes. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Bakgrund: Androgen alopeci är ett tillstånd där individen tappar hår även kallat ärftligt håravfall. Utseende idag är mycket viktig och androgen alopeci i tidig ålder kan påverka självförtroende hos en individ. Det kan leda till sämre livskvalitet samt depression och stress. Androgen alopeci beror på att androgena receptorer i hårfollikeln aktiveras av dihydrotestosteron (DHT) och resultatet blir att follikeln krymper ihop och slutar växa. DHT är en starkare form av testosteron. För att behandla androgen alopeci används 5α reduktashämmare som hämmar ett enzym som omvandlar testosteron till DHT och nivån av DHT sänks i serum och mindre antal androgena receptorer aktiveras. Detta kan leda till biverkningar som erektil dysfunktion (ED), ejakulationsrubbningar och minskad libido. Syfte: Syftet med arbetet var att jämföra effekten hos de två 5α reduktashämmarna finasterid och dutasterid samt jämföra risk för biverkningar. Metod: Detta arbete skrevs med hjälp av kliniska studier hämtade från sökmotorn pubmed med sökord som ”Androgenic alopecia, finasteride, dutasteride, adverse effects”. Resultat: Dutasterid sänkte halten DHT i serum som högst med 96% medan finasterid sänkte som högst med 73%. Detta bidrog till mer effektiv hårtillväxt vid användning av dutasterid. Risken för biverkningar var högre vid användning av dutasterid än finasterid. Skillnaden var störst vid ED där vid behandling av 14 personer med dutasterid orsakar ett utfall av ED, jämfört med finasterid där ED endast upplevdes 1 på 200. Slutsats: Dutasterid verkar vara det bättre alternativet för hårtillväxt vid androgen alopecia. De visade på sammantagna resultaten med dutasterid visade större tillväxt av hår på hjässan i vertex jämfört med finasterid. Dessa 5α reduktashämmare är inga mirakelmediciner mot androgen alopeci men kan ge en del hår tillbaka och fungerar genom att bromsa ytterligare håravfall. / Androgenic alopecia, also called male pattern hair loss (MPHL) can be a difficult condition in today’s society which is focused much on looks and appeal. This can lower a person’s quality of life, increase stress and lead to depression. Androgenic alopecia is affected by androgenic receptors that are being activated by dihydrotestosterone (DHT) in the hair follicle. This leads to miniaturizing of the hair follicle and the hair cycle stops. The 5α reductase inhibitors finasteride and dutasteride block enzymes that convert testosterone to DHT which lowers the concentration of DHT in serum. This can cause side effects like erectile dysfunction (ED), difficulties with ejaculation and decreased libido. The purpose of this report is to evaluate which of the drugs finasteride and dutasteride is the better choice for fighting hair loss and investigate the risk of getting side effects. The clinical trials used in this report are from the database Pubmed and was found using search terms “androgenic alopecia, finasteride, dutasteride adverse effects.” The result from this report showed that dutasteride lowered the serum DHT most at 96% and finasteride 73% at best. The lower the serum DHT was the more hair was growing back on vertex. Dutasteride had higher risk of causing side effects, the biggest difference was in ED where 1 in 14 would get this side effect compared to finasteride 1 in 200. The conclusion of this report is that none of the drugs truly cures androgenic alopecia but can help maintain and, in most cases regrow some hair. The best drug for fighting hair loss is dutasteride but one shall be aware of side effects.