Abstract Chlamydiae are obligatory intracellular gram-negative bacteria with a unique growth cycle. They are very successful pathogens and responsible for a wide variety infections in humans and different animal species. In addition, they have a tendency to cause recurrent, persistent or chronic infections with potentially severe sequelae years or decades later. The general purpose of this work was to study the possible serological associations between chronic chlamydial infection, systemic inflammation and reproductive health in a general population. The chlamydial heat shock proteins 60 and 10 (Hs10 and Hsp60) have been suggested to contribute to the pathogenesis of chronic chlamydial infections. Thus, the antibodies to chlamydial Hsp10 and Hsp60 were also investigated in complications of pregnancy. The present study was a longitudinal population-based birth cohort study, and all of the original papers of this dissertation are based on a nested case - control design. Our results confirmed the serological association between C. trachomatis infections and subfertility and the rather high incidence of undiagnosed C. trachomatis infections in the male partners of subfertile couples. We further demonstrated a serological association between previous C. trachomatis infections, immunity to chlamydial Hsps and female subfertility. We also showed that serological markers of chronic chlamydial infection present as early as the first trimester are associated with preterm delivery among nulliparous women. When elevated levels of C. trachomatis IgG and hsCRP were present, the estimated risk for preterm delivery was over 4-fold. According to our study, nulliparous women who subsequently developed preeclampsia leading to preterm delivery, which was used as a marker of more serious illness, had significantly more often serum IgG antibodies to C. pneumoniae during the first trimester of pregnancy compared to the preeclamptic women who delivered at term. In conclusion, chronic C. trachomatis infection was found to associate with subfertility both in men and in women. In addition, a subclinical chronic inflammatory process associated at least partly with chronic C. trachomatis infection and present in the first trimester already may be important in the development of preterm delivery. Chronic C. pneumoniae infection and systemic low-grade inflammation were found to associate with pregnancies that lead to preeclampsia and preterm delivery.

Background: This thesis is based on a randomised controlled trial comparing the effectiveness of intrauterine insemination (IUI) plus Controlled Ovarian Hyperstimulation (COH) versus in vitro fertilisation (IVF) as the first line treatment option for couples with unexplained subfertility. Subfertility of a couple is classed as unexplained when they fail to conceive after one year of regular unprotected intercourse and when all the standard investigations for ovulation, tubal patency and semen analysis have been found to be normal. It affects 30-40% of couples. The age-old methods of treating these couples have included the empirical use of clomiphene or gonadotrophins to correct any possible subtle defects in ovulation with or without IUI (to overcome any existing cervical barrier to natural conception) or IVF. However, the best treatment options for these couples have yet to be determined. The matter has been made even more controversial by the issue of NICE (National Institute for Health and Care Excellence) guidelines in the UK that suggest IUI be abandoned completely for these women in favour of IVF after 2 years of expectant management. A systematic review of the available literature comparing IUI + COH versus IVF for unexplained subfertility revealed limited numbers of available studies and high clinical and statistical heterogeneity among them. An online survey was also conducted among fertility specialists to establish the general consensus regarding management of such couples. The results revealed a lack of agreement among fertility specialists with regards to the first line treatment of couples with unexplained subfertility. The mixed 8 response to this survey demonstrated the ongoing dilemma among practitioners, much of which was due to the lack of robust evidence. A randomised controlled trial was then designed to examine the effectiveness of COH with gonadotrophins + IUI versus IVF as the first line approach to the treatment of unexplained subfertility (Figure 1). This was the first UK-based randomised controlled trial comparing these two first-line management options for unexplained subfertility.

Contexte : Une amélioration des habitudes de vie, avec une légère perte pondérale (5 %), augmenterait les chances de concevoir un enfant chez les femmes obèses souffrant d’infertilité. La perte de poids est considérée comme le principal déterminant de la survenue d’une grossesse, mais aucune étude n’a évalué le rôle la qualité alimentaire. Objectif principal : Évaluer l’impact de l’amélioration de la qualité alimentaire sur les chances de survenue d’une grossesse auprès de femmes obèses et infertiles. Méthodologie : Étude prospective s’insérant dans un essai randomisé contrôlé évaluant l'impact d'une intervention interdisciplinaire visant l’amélioration des habitudes de vie sur la fertilité des femmes obèses suivies à la clinique de fertilité du CHUS en comparaison à des femmes ayant accès aux soins standards en fertilité seulement (n = 102). Des visites de recherche ont lieu à l’entrée de l’étude puis aux 6 mois jusqu’à la fin du projet, soit après 18 mois ou jusqu’à l’accouchement. La collecte de données inclut un questionnaire de fréquence alimentaire, des mesures anthropométriques et un test de condition physique. Un index de qualité alimentaire, le Healthy Eating Index modifié (mHEI, 0-100 points), a été calculé. Résultats : Pour l’ensemble des participantes, l’amélioration de la qualité alimentaire n’était pas associée à de meilleures chances de grossesse. À l’aide d’un modèle de régression de Cox, il a été possible d’observer que la qualité alimentaire initiale était un prédicteur important de grossesse au sein des deux groupes confondus (HR (par 10 unités) : 1,24 [1,03 – 1,50], p = 0,027), indépendamment du niveau de condition physique et de l’anthropométrie. De façon similaire, une meilleure qualité alimentaire observée avant conception présentait une association significative indépendante avec les chances de concevoir dans le temps (HR (par 10 unités) : 1,25 [1,04 – 1,49], p = 0,017). Les variables anthropométriques, incluant le poids, n’étaient pas associées à une probabilité accrue de concevoir. Conclusion : Une meilleure qualité alimentaire en préconception augmenterait les chances de grossesse chez les femmes infertiles souffrant d’obésité. / Abstract : Background : Improvement of lifestyle habits, associated with a modest weight loss (5 %), has shown to increase odds of pregnancy in overweight and obese women diagnosed with infertility. Weight loss is considered as the main factor that explains the improvement of fertility, but no study evaluated the specific role of diet quality on fertility in this population. Objective : Evaluate the impact of improving diet quality on odds of pregnancy in obese and infertile women seeking for fertility treatments. Methods : Prospective study nested in a randomized controlled trial evaluating the impact of an interdisciplinary lifestyle intervention on fertility of obese women followed at the fertility clinic of the CHUS, in comparison to standard fertility care only. Research visits take place every 6 months until the end of the project, which is after 18 months or delivery. Data collection include a food frequency questionnaire, anthropometric measurement and a fitness evaluation. A score of diet quality, the modified Healthy Eating Index (mHEI, 0-100 units), was calculated. Results : For all the participants, improvement of diet quality was not associated with the probability of pregnancy. With Cox regression, we observed that the initial diet quality was an important predictor of pregnancy within the two confounded groups (HR (by 10 units) : 1.24 [1.03 – 1.50], p = 0.027), independently of cardiorespiratory fitness and anthropometry. Similarly, the best diet quality observed before conception presented a significant independent association with odds of pregnancy over time (HR (by 10 units) : 1.25 [1.04 – 1.49], p = 0.017). Anthropometric variables, including weight, were not associated with a higher probability of conception. Conclusion : A greater diet quality in preconception seems to increase probability of pregnancy in obese infertile women.

Abstract Uterine leiomyomas are the most common benign tumours in females. They are myometrial neoplasms, may present single or multiple, and may be located in various sites of the uterus. Leiomyomas distort the uterine cavity and the uterus itself, causing abnormal vaginal bleeding, reduced fertility and also pelvic pressure and pain symptoms. The aim of this study was to elaborate current knowledge on familial uterine leiomyomas and to explore the possible association between uterine leiomyoma and cardiovascular disease risk factors, and also the association between leiomyomas and endometriosis. The natural history of familial uterine leiomyoma study showed significant differences between familial and non-familial leiomyoma cases, familial cases having more severe clinical characteristics. They presented with multiple uterine leiomyomas and were more often symptomatic. They were also diagnosed at a younger age. The prevalence study on uterine leiomyomas and endometriosis offered confirmation of an association between the diseases. Uterine leiomyomas and endometriosis seem to decrease female fertility independently of each other. Uterine leiomyomas related to the hereditary leiomyomatosis and renal cell cancer (HLRCC) tumour syndrome were studied in regard to their clinical characteristics and immunophenotype. The study provided evidence that women with HLRCC may be identified through distinct leiomyoma clinical characteristics, and routine-use IHC of CD34 and Bcl-2. Distinguishing these leiomyoma cases from sporadic ones may identify families affected by fumarate hydratase (fumarase, FH) mutation. Uterine leiomyoma and cardiovascular disease risk factors were studied in The Northern Finland Birth Cohort 1966 (NFBC1966). The study showed an association between leiomyomas and raised cardiovascular disease risk factors, serum lipids and metabolic syndrome in particular. These findings may suggest that there are shared predisposing factors underlying both uterine leiomyomas and adverse metabolic and cardiac disease risks, or that metabolic factors have a role in biological mechanisms underlying leiomyoma development. This study provides novel information on clinical characteristics of familial uterine leiomyomas and on the immunophenotype of HLRCC-related leiomyomas. The study also offers significant confirmation of associations between uterine leiomyomas and both endometriosis and several CVD risk factors. / Tiivistelmä Kohdun leiomyoomat ovat naisten yleisin hyvänlaatuinen kasvain. Ne ovat myometriumin neoplastisia muutoksia ja ne ilmenevät joko yksittäisinä tai monilukuisina, ja ne voivat sijaita missä tahansa kohdun myometriumia. Leiomyoomat muuttavat kohdun ja kohtuontelon säännöllistä muotoa. Lisäksi ne aiheuttavat vuotohäiriöitä, alentunutta hedelmällisyyttä, ja lantion alueen painetta ja kipua. Tämän tutkimuksen tavoitteena oli laajentaa nykyistä tietämystä suvuittain esiintyvistä kohdun leiomyoomista ja selvittää mahdollista leiomyoomien ja kardiovaskulaaritautiriskin assosiaatiota, ja lisäksi selvittää leiomyoomien ja endometrioosin assosiaatiota. Suvuittain esiintyvien kohdun leiomyoomien taudinkulkua selvittävässä tutkimuksessa osoitettiin merkittäviä eroja suvuittain ja ei-suvuittain esiintyvien leiomyoomien välillä. Suvuittain esiintyvien leiomyoomien kliininen taudinkuva oli vaikeampi, leiomyoomia oli kohdussa useampia ja ne aiheuttivat useammin oireita ja lisäksi ne diagnosoitiin nuoremmalla iällä. Kohdun leiomyoomien ja endometrioosin yleisyyttä selvittävä tutkimus antoi lisävahvistusta sille havainnolle, että nämä taudit assosioivat keskenään. Tutkimustuloksen mukaan leiomyoomat ja endometrioosi vähentävät naisen hedelmällisyyttä toisistaan riippumatta. Perinnöllinen kohdun leiomyomatoosi ja munuaissyöpä (hereditary leiomyomatosis and renal cell cancer, HLRCC) -kasvainoireyhtymään liittyvän kohdun leiomyoomia selvittävän tutkimuksen tuloksien mukaan HLRCC-naisten kohdun leiomyoomien kliiniset ominaisuudet poikkeavat satunnaisesti esiintyvien leiomyoomien ominaisuuksista. Naisella HLRCC voitaisiinkin tunnistaa näiden poikkeavien ominaisuuksien perusteella, sekä immunohistokemiallisilla värjäyksillä CD34 ja Bcl-2. Fumaraattihydrataasi (fumaraasi, FH) -geenin mutaatiota kantava suku voitaisiin siten tunnistaa yksittäisen HLRCC leiomyoomatapauksen avulla. Pohjois-Suomen syntymäkohortti 1966 (Northern Finland Birth Cohort 1966, NFBC1966) tutkittiin kohdun leiomyoomia ja kardiovaskulaarisairauden riskitekijöitä. Tutkimustuloksien perusteella kohdun leiomyoomat assosioivat koholla olevien kardiovaskulaarisairauden riskien kanssa, erityisesti seerumin lipidien ja metabolisen syndrooman suhteen. Näiden tutkimustulosten perusteella voidaan esittää, että leiomyoomien ja terveydelle epäedullisen metabolian ja kardiovaskulaaritaudin riskien taustalla on mahdollisesti joitain yhteisiä altistavia tekijöitä, tai että metabolisilla tekijöillä on rooli kohdun leiomyoomien tautimekanismissa. Tämä tutkimus on tuottanut uutta tietoa suvuittain esiintyvien kohdun leiomyoomien kliinisestä taudinkuvasta ja HLRCC:n liittyvien leiomyoomien immunofenotyypistä. Lisäksi tämä tutkimus esittää lisävahvistusta kohdun leiomyoomien ja endometrioosin assosiaatiolle sekä useille kardiovaskulaaririskitekijöille.