The wave-like developmental pattern of follicles ≥1 mm in temporal relationship with follicle stimulating hormone (FSH) and the existence of 2- and 3-waves of follicular development during an interovulatory interval (IOI) have been clearly defined in cattle. However, information about the developmental pattern of antral follicles <1 mm and the repeatability of the wave pattern (2- or 3-wave IOI) is lacking. Using approaches such as immunization against GnRH (to suppress circulating concentrations of FSH) and histomorphometric study of ovarian tissues collected from cyclic heifers on different days after ovulation, the developmental pattern of antral follicles <1 mm and the role of FSH in their development were studied in heifers. Ultrasonographically acquired follicular data were used to determine the repeatability of 2- and 3-wave patterns and the effect of season on the wave patterns. The ovulatory follicle in 3-wave IOI is exposed to a shorter term high-progesterone environment than that of 2-wave IOI, and it has been argued that the less-aged ovulatory follicle of 3-wave IOI yields a more fertile oocyte than the 2-wave IOI. The developmental competence of oocytes in preovulatory follicles of 2- versus 3-wave IOI was compared using in vivo environments created to mimic short-term low- and high-progesterone environments similar to 2- and 3-wave IOI, respectively. The developmental competence of oocytes in persistent dominant-type follicles was also determined.<p>The vaccination against GnRH attenuated FSH surges but did not suppress the basal circulating concentrations of FSH. The attenuation of FSH surges suppressed the wave-like emergence of follicles ≥4 mm but not of the antral follicles <4 mm. The study revealed an inverse relationship between the mean and peak circulating concentrations of FSH and the number of follicles recruited into ≥1 mm size category. Histomorphometric study revealed that antral follicles <1 mm developed in a wave-like fashion in response to a rise in the circulating concentrations of FSH. After treatment with exogenous FSH, the growth rate of follicles in GnRH-immunized heifers was similar to controls. <p>The duration of IOI was predictive of the wave pattern (i.e., 2- or 3-wave IOI), and the pattern was repeatable within individuals throughout the year. The dominant follicle of Wave 1 in 2-wave IOI had a longer duration of dominance than in 3-wave IOI. Hence, the dominant follicle of Wave 1 may have a primary role in the regulation of 2- and 3-wave patterns. Greater attrition of follicles in 3-wave IOI, due to the emergence of an extra wave compared to 2-wave IOI, may contribute to earlier follicular depletion and onset of reproductive senescence in heifers with primarily a 3-wave pattern. The fertilization capacity of oocytes that were exposed to the short-term low-progesterone environment (i.e., similar to the early growing phase of the ovulatory follicle of 3-wave IOI) was increased, but the developmental competence post-fertilization was not different from oocytes that were exposed to a short-term high-progesterone environment (i.e., similar to the early growing phase of preovulatory follicle of 2-wave IOI). Multiple follicles developed under the prolonged-low progesterone environment, but failed to ovulate.

Studies of prophylactic salpingectomy specimens from BRCA1/2 mutation carriers, at risk for tubal and ovarian high-grade serous carcinoma (SerCa), have consistently revealed occult carcinomas and putative histological cancer precursors in the distal fallopian tube epithelium (FTE), supporting the FTE as the source of SerCa. In this thesis I molecularly characterized and compared non-malignant FTE from mutation carriers (FTEb) and control patients (FTEn) to identify alterations that may predispose to malignant transformation. Gene expression profiling of laser capture microdissected FTEn, FTEb and SerCa indicated that SerCa have similar molecular profiles whether of presumed ovarian or tubal origin, supporting the notion they share a common cell of origin within the FTE. Furthermore, FTEb samples obtained during the post-ovulatory luteal phase showed gene expression profiles closely resembling SerCa samples, suggesting that the luteal phase milieu may contribute to serous carcinogenesis. An initial hypothesis was that FTEb may respond differently to luteal progesterone compared to FTEn, via differential expression of progesterone receptor (PR) isoforms. However, similar relative isoform expression in FTEn and FTEb samples suggested that a luteal phase-associated factor other than progesterone directs gene expression changes in FTEb. The possibility that FTEb respond differently to ovulation-associated inflammatory cytokines that are locally elevated during the luteal phase was next investigated. Importantly, FTEb specimens previously found to cluster with SerCa based on their global gene expression profiles showed evidence of increased nuclear factor-κB (NFκB)-dependent (pro-inflammatory) signalling and diminished glucocorticoid receptor (GR)-dependent (anti-inflammatory) signalling. Furthermore, I demonstrate that disabled homolog 2 (DAB2), an adaptor molecule decreased in SerCa and FTE luteal samples, enhances both GR-mediated transactivation and suppression of NFκB signalling, implicating DAB2 as a crucial determinant of inflammatory signalling and ovarian cancer risk. Altogether, this thesis identifies gene expression changes in FTE from BRCA mutation carriers during the post-ovulatory luteal phase that parallel those detected in SerCa. The data support a proposed novel testable model for predisposing events contributing to SerCa that centres on an altered ability to quickly resolve the pro-inflammatory environment created by the ovulatory event.

Women are twice as likely as men to suffer from depression and anxiety disorders and have an increased risk of onset during periods associated with hormonal changes, such as the postpartum period and the menopausal transition. Furthermore, some women seem more sensitive to normal hormone fluctuations across the menstrual cycle, since approximately 3-5% suffers from premenstrual dysphoric disorder (PMDD). Why these disorders are so common in women has not been established but there is a probable involvement of the ovarian hormones. The aim of this thesis was to investigate the effect of the ovarian hormones on the female brain during different reproductive states using psychological tests known to affect brain activity in different ways. Paper one examined the effect of the ovarian hormones on prepulse inhibition (PPI) on the acoustic startle response (ASR) and comprised cycling women and postmenopausal women. The cycling women had lower levels of PPI compared to postmenopausal women and postmenopausal women with moderate estradiol levels had lower PPI compared to postmenopausal women with low estradiol levels. Paper two examined the effect of anticipation and affective modulation on the ASR in women with PMDD and healthy controls. Women with PMDD have an increased modulation during anticipation of affective pictures compared to healthy controls during the luteal phase of the menstrual cycle. Paper three examined brain activity during response inhibition among women with PMDD and healthy controls by the use of a Go/NoGo task and fMRI. Women with PMDD displayed a decreased activity in the left insula during follicular phase and an increased activity during the luteal phase compared to controls. Paper four comprised women in the postpartum period and non-pregnant controls to examine brain activity during response inhibition. While this study revealed decreased activity at 4 weeks postpartum compared to 48 hours postpartum we cannot ascertain the role of the ovarian steroids, since none of the significant brain areas correlated with ovarian steroid or neurosteroid serum concentrations. The results of this thesis demonstrate that the ovarian hormones, or at least various hormonal states, have a probable impact on how the female brain works.

The wave-like developmental pattern of follicles ≥1 mm in temporal relationship with follicle stimulating hormone (FSH) and the existence of 2- and 3-waves of follicular development during an interovulatory interval (IOI) have been clearly defined in cattle. However, information about the developmental pattern of antral follicles <1 mm and the repeatability of the wave pattern (2- or 3-wave IOI) is lacking. Using approaches such as immunization against GnRH (to suppress circulating concentrations of FSH) and histomorphometric study of ovarian tissues collected from cyclic heifers on different days after ovulation, the developmental pattern of antral follicles <1 mm and the role of FSH in their development were studied in heifers. Ultrasonographically acquired follicular data were used to determine the repeatability of 2- and 3-wave patterns and the effect of season on the wave patterns. The ovulatory follicle in 3-wave IOI is exposed to a shorter term high-progesterone environment than that of 2-wave IOI, and it has been argued that the less-aged ovulatory follicle of 3-wave IOI yields a more fertile oocyte than the 2-wave IOI. The developmental competence of oocytes in preovulatory follicles of 2- versus 3-wave IOI was compared using in vivo environments created to mimic short-term low- and high-progesterone environments similar to 2- and 3-wave IOI, respectively. The developmental competence of oocytes in persistent dominant-type follicles was also determined.<p>The vaccination against GnRH attenuated FSH surges but did not suppress the basal circulating concentrations of FSH. The attenuation of FSH surges suppressed the wave-like emergence of follicles ≥4 mm but not of the antral follicles <4 mm. The study revealed an inverse relationship between the mean and peak circulating concentrations of FSH and the number of follicles recruited into ≥1 mm size category. Histomorphometric study revealed that antral follicles <1 mm developed in a wave-like fashion in response to a rise in the circulating concentrations of FSH. After treatment with exogenous FSH, the growth rate of follicles in GnRH-immunized heifers was similar to controls. <p>The duration of IOI was predictive of the wave pattern (i.e., 2- or 3-wave IOI), and the pattern was repeatable within individuals throughout the year. The dominant follicle of Wave 1 in 2-wave IOI had a longer duration of dominance than in 3-wave IOI. Hence, the dominant follicle of Wave 1 may have a primary role in the regulation of 2- and 3-wave patterns. Greater attrition of follicles in 3-wave IOI, due to the emergence of an extra wave compared to 2-wave IOI, may contribute to earlier follicular depletion and onset of reproductive senescence in heifers with primarily a 3-wave pattern. The fertilization capacity of oocytes that were exposed to the short-term low-progesterone environment (i.e., similar to the early growing phase of the ovulatory follicle of 3-wave IOI) was increased, but the developmental competence post-fertilization was not different from oocytes that were exposed to a short-term high-progesterone environment (i.e., similar to the early growing phase of preovulatory follicle of 2-wave IOI). Multiple follicles developed under the prolonged-low progesterone environment, but failed to ovulate.

Veterinært speciale, 27 ECTS point. / Haves kun i elektronisk udg.

Ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE), but it is often diagnosed during the late stages and therefore the events that contribute to the initiation and progression of ovarian cancer are poorly defined. Epidemiological studies have indicated an association between the female reproductive hormones and ovarian cancer etiology, but the direct effects of 17β-estradiol (E2), progesterone (P4), luteinizing hormone (LH) and follicle stimulating hormone (FSH) on disease pathophysiology are not well understood. A novel transgenic mouse model of ovarian cancer was generated that utilized the Cre/loxP system to inducibly express the oncogene SV40 large and small T-Antigen in the OSE. The tgCAG-LS-TAg mice developed poorly differentiated ovarian tumours with metastasis and ascites throughout the peritoneal space. Although P4 had no effect; E2 significantly accelerated disease progression in tgCAG-LS-TAg mice. The early onset of ovarian cancer was likely mediated by E2’s ability to increase the areas of putative preneoplastic lesions in the OSE. E2 also significantly decreased survival time in ovarian cancer cell xenografts. Microarray analysis of the tumours revealed that E2 mainly affects genes involved in angiogenesis and cellular differentiation, proliferation, and migration. These results suggest that E2 acts on the tumour microenvironment in addition to its direct effects on OSE and ovarian cancer cells. In order to examine the role of the gonadotropins in ovarian cancer progression, the tgCAG-LS-TAg mice were treated with 4-vinylcyclohexene-diepoxide (VCD) to induce menopause. Menopause slowed the progression of ovarian cancer due to a change in the histological subtype from poorly differentiated tumours to Sertoli tumours. Using a transgenic mouse model, it was shown that E2 accelerated ovarian cancer progression, while P4 had little effect on the disease. Menopause (elevated levels of LH and FSH) altered the histological subtype of the ovarian tumours in the tgCAG-LS-TAg mouse model. These results emphasize the importance of generating animal models to accurately recapitulate human disease and utilizing these models to develop novel prevention and treatment strategies for women with ovarian cancer.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Medical College of Ohio, 2004. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Sciences." Major advisor: Manohar Ratnam. Includes abstract. Document formatted into pages: iii, 293 p. Title from title page of PDF document. Includes bibliographical references (p. 175-281).

Hormonal-mediated uterine quiescence involves the maintenance of a decreased inflammatory responsiveness. However, no study has investigated whether labor induction with prostanoids is associated with changes in maternal serum hormones. The objective of this study was to determine whether changes in circulating levels of progesterone, estradiol and estriol from admission to delivery are associated with successful labor induction with dinoprostone. A cohort of 81 pregnant women at term was followed from admission to birth until delivery, during the period of 2010-2011. The study was performed at the Hospital of the Federal University of Santa Maria, a tertiary care hospital. Unselected subjects were recruited and blood samples were obtained at admission and immediately before delivery. Sixteen patients had vaginal delivery after spontaneous labor, 12 required emergency cesarean after spontaneous labor and 16 underwent elective cesarean. Thirty-seven patients had labor induction with dinoprostone. Eligible patients received a vaginal insert of dinoprostone (10 mg), and patients were followed up until delivery. Progesterone (P4), estradiol (E2) and estriol (E3) plasma level and P4/E2, P4/E3 and E3/E2 ratio changes were observed from admission to immediately before birth, and the association of these measures with the resulting clinical classification outcome (route of delivery and induction responsiveness) were assessed. Progesterone plasma level decreased from admission to delivery in patients who underwent successful labor induction with dinoprostone [vaginal and cesarean delivery after induced labor: 23% (P<0.001) and 18% (P<0.025) decrease, respectively], but not in those whose induction failed (6.4% decrease, P>0.05). Estriol and estradiol levels did not differ between groups. Successful dinoprostone-induced labor was associated with maternal progesterone level decrease along time. While a causal relationship between progesterone decrease and effective dinoprostone-induced labor can not be established, it is tempting to propose that it may contribute for progesterone withdrawal and favor labor induction in humans. / A quiescência uterina mediada por hormônios envolve a manutenção de uma responsividade inflamatória reduzida. Contudo, nenhum estudo investigou se a indução do parto com prostanóides está associada com alterações em hormônios séricos maternos. Os objetivos deste estudo foram determinar se as alterações nos níveis circulantes de progesterona, estradiol e estriol desde a admissão até o parto estão associados à indução bem sucedida do parto com dinoprostona. Uma coorte de 81 mulheres grávidas a termo foi acompanhada desde a admissão até o parto, durante o período de 2010-2011. O estudo foi realizado no Hospital da Universidade Federal de Santa Maria, um hospital de cuidados terciários. Indivíduos não selecionados foram recrutados e amostras de sangue foram obtidas na admissão e imediatamente antes do nascimento. Dezesseis pacientes tiveram parto vaginal após trabalho de parto espontâneo, 12 necessitaram a realização de cesariana de emergência após trabalho de parto espontâneo e 16 foram submetidas à cesárea eletiva. Trinta e sete pacientes tiveram indução de trabalho de parto com dinoprostona. As pacientes elegíveis receberam um pessário de inserção vaginal de dinoprostona (10 mg), e foram acompanhadas até o parto. Os níveis plasmáticos de progesterona (P4), estradiol (E2) e estriol (E3) e as relações P4/E2, P4/E3 e E3/E2 foram observadas da admissão até imediatamente antes do nascimento, e a associação destas medidas com a classificação clínica resultante foi avaliada (via de parto e resposta à indução). Os níveis plasmáticos de progesterona diminuíram desde a admissão até o nascimento em pacientes que responderam à indução com dinoprostona [parto vaginal e cesáreo após trabalho de parto induzido: redução de 23% (P<0.001) e 18% (P<0.025), respectivamente], mas não nos quais a indução falhou (redução de 6.4%, P>0.05). Os níveis de estriol e estradiol, e as relações P4/E2, P4/E3 e E3/E2 não foram diferentes entre os grupos. O sucesso da resposta à indução de parto com dinoprostona esteve associado com a redução no nível de progesterona materna ao longo do tempo. Enquanto uma relação causal entre a redução na progesterona e o trabalho de parto efetivo induzido pela dinoprostona não pode ser estabelecida, é tentador propor que possa contribuir para a retirada da progesterona e favorecer a indução do parto em humanos.