BACKGROUND: Current estimates indicate approximately 6.7% of women in the US are infertile. Infertility can arise from many different conditions and can be both attributed to male and female factors. In women, measures of ovarian reserve such as AMH level or FSH level on day three of the menstrual cycle can be used to predict reproductive success. In conjunction with additional tests and lifestyle screening, these values help to guide the course of treatment, with some patients moving eventually to in vitro fertilization. In vitro fertilization therapy is cost-prohibitive if the patient does not have insurance coverage, an issue for the majority of patients across the United States. AIMS: To evaluate the correlation between cycle number, age, and AMH level with achieving a successful live birth through a statistical analysis of over 50,000 cycles of in vitro fertilization. Methods: Data was obtained from Practice Highway, a company that owns the electronic medical record (EMR) program eIVF, used by over 140 reproductive endocrinology practices across the country. The database provided a total of 88 variables and 138,526 IVF cycle observations ranging from 01/01/2005 to 09/09/2015. A thorough review of available literature was performed to determine the need for the correlations analyzed in this paper. Utilizing this information in conjunction with the scope of this paper, the number of variables was reduced to four. Linear regression and multivariate regression was performed on the four main study variables to identify possible correlations. Results: The results of our study indicate that there is not a strong correlational relationship between the variables analyzed. There was not a significant correlation between age and whether a live birth was achieved. As expected, the strongest relationship identified through our study is the decrease in AMH as age increases. Conclusions: Our study results indicate that there is no correlation between AMH and live birth, suggesting that this biomarker alone is insufficient to be used by physicians as a means of advising patients on IVF success. Additionally, measures such as number of cycles completed and age at cycle start can be useful when counseling patients on their probability of success with assisted reproductive technologies.

I tidigare debatter om marknadseffektivitet har diskussioner förts mellan två läger där den ena sidan hävdat att marknaden är effektiv och den andra sidan, ofta med säte i ekonomisk beteendevetenskap, hävdat att systematisk riskjusterad överavkastning går att erhålla. På senare år har diskussionen utvecklats till att utröna om och hur graden av marknadseffektivitet förändras över tid. Den andra sidan gör nu kopplingen att Effektiva marknadshypotesen, en av de ekonomiska teorier som fått störst genomslag, kan samexistera med ekonomisk beteendevetenskap och förklarar att graden av marknadseffektivitet förändras över tid. Denna koppling kallas för Adaptiva marknadshypotesen och är i stor utsträckning vad denna uppsats kommer att behandla. En effektiv marknad innebär att aktiekursen alltid återspeglar det sanna värdet av företaget. En privat investerare gynnas på så sätt av en effektiv marknad då en aktie inte kan vara felaktigt prissatt. I en ineffektiv marknad kan investerare som är duktiga på aktieanalys erhålla systematisk riskjusterad överavkastning. Relativ styrka är en välkänd strategi för aktiehandel som sägs generera riskjusterad överavkastning. Relativ styrka investerar i ett urval av de historiskt bäst presterande aktierna och avyttrar dem en period senare. Tanken är att aktierna ska fortsätta sin positiva utveckling under denna period. I denna uppsats konstrueras en modell med relativ styrka som grund för aktieurval för att mäta graden av riskjusterad överavkastning som går att erhålla med strategin. Detta mått kallas för Alpha. Förändras Alpha över tid som Adaptiva marknadshypotesen förespråkar? Finns det skillnader i hur Alpha förändras över tid mellan segment på börsen? Dessa är några av frågorna som undersöks i studien. Studien bygger på ett kvantitativt tillvägagångssätt med en population av aktier som ingår i Nasdaq OMX Nordic. Aktiepopulationen har delats upp i tre storleksbaserade segment; Large-, Mid- och Small Cap samt ett fjärde segment sammanslaget av de tre förstnämnda segmenten. Undersökningsperioden sträcker sig mellan 2002-10-03 till 2013-05-01 och innefattar tre olika marknadsklimat. Resultaten indikerar att marknadseffektivitet bör betraktas som ett dynamiskt begrepp. Det finns en negativ korrelation mellan några av de observerade segmenten som forskarna tror kan förklaras av att anomalier uppstår och försvinner med jämna mellanrum. Detta gör att analytiker och aktörer på marknaden flyttar sitt fokus till segmentet där anomalin uppstått i hopp om generera avkastning på den felaktiga prissättning som anomalin gett upphov till. I takt med att anomalin utnyttjas så försvinner den från marknaden vilket kan vara en förklaring till varför graden av marknadseffektivitet varierar.

La chimiothérapie induit une baisse de la fertilité en exerçant une toxicité directe sur les ovaires entrainant une diminution du stock ovocytaire. Couramment utilisé dans le traitement du cancer du sein, le cyclophosphamide (Cy) est une des drogues reconnue comme la plus gonadotoxique. Récemment, il a été proposé que le Cy provoquait une déplétion folliculaire par une entrée en croissance massive des follicules au repos. L’Hormone Anti-Müllérienne (AMH) étant un des facteurs régulant la sortie des follicules primordiaux de la réserve ovarienne, nous avons émis l’hypothèse que cette hormone pourrait limiter la gonadotoxicité du Cy. Nous avons montré qu’un traitement par AMH recombinante chez des souris pubères traitées par Cy, permettait effectivement de limiter la déplétion folliculaire. Sur le plan fondamental, nous avons mis en évidence que l’autophagie pouvait être un des mécanismes impliqués dans l’inhibition du recrutement folliculaire exercée par l’AMH. Enfin, la méthode de référence consistant à évaluer la réserve ovarienne chez la souris étant particulièrement longue et fastidieuse, nous avons développé une technique de comptage folliculaire automatisé en utilisant des méthodes d’intelligence artificielle, et plus particulièrement une approche de « deep learning». / Chemotherapy induces infertility by exerting a direct toxicity on the ovaries, resulting in a depletion of the follicular stockpile. Cyclophosphamide (Cy), widely used for breast cancer, is recognized as one of the most gonadotoxic agent. Recently, it has been proposed that Cy gives rise to follicular depletion by a massive growth of resting follicles which are then destroyed. Since Anti-Müllerian Hormone (AMH) is one of the factors regulating primordial follicles activation, we hypothesized that this hormone might limited Cy-induced gonadotoxicity. We have shown in pubertal mice that recombinant AMH injections are able to preserve primordial follicle loss Cy-induced and might improve fertility outcome after treatment. In addition, we provide evidence that autophagy could be one of the mechanisms involved in the inhibition of follicular recruitment by AMH. At least, nowadays, the “gold standard” method of evaluating ovarian reserve in mouse is a process particularly time-consuming and tedious. We developed a new methodology of automatic primordial follicles detection and counting within mouse ovaries, using modern artificial intelligence methods, especially deep learning approach.

Background: Due to the “flare effect” associated with the flare protocol, variation in the degree of follicular maturation during stimulation may result in differences in follicle response as compared to the luteal protocol which is based on maximal pituitary suppression and synchronization of follicular maturation. In this study, besides other methods, Anti-Mullerian Hormone (AMH), a novel marker for ovarian reserve, was used as a tool to evaluate the ovarian responsiveness to stimulation. Methods: Women undergoing IVF/ICSI treatment in the UBC IVF Program from January to December 2006 using luteal and flare protocols were retrospectively selected for a total of 40 treatment cycles, 20 cycles in each protocol matched by age, weight, and indication for IVF/ICSI. Serial serum Estradiol (E₂) levels and follicle data were obtained from the clinic chart. Follicle stimulating hormone (FSH), Luteinizing Hormone (LH), progesterone (P), androstenedione (D₄) and AMH levels were measured from aliquots of frozen serum samples. Hormone responses were evaluated by Area Under the Curve (AUC). Data were analyzed using the t-test and statistical significance was considered present at P<0.05. Results are reported as the mean ± SEM. Results: For flare versus luteal protocol, there was a significant difference in the number of total follicles (14.5 ± 1.8 vs 21.3 ± 2.3), medium follicles (3.7 ± 0.6 vs 8.4 ± 1.3), eggs retrieved (8 ± 0.8 vs 14 ± 1.4) and oocytes fertilized (4.4 ± 0.5 vs 8.4 ± 0.7), AMH AUC (62 ± 12 vs 111 ± 13), LH AUC (67 ± 21 vs 20 ± 9), FSH AUC (171 ± 59 vs 112 ± 29), respectively. Mean number of embryos transferred in both groups was similar. Number of pregnancies conceived (5 for flare and 10 for luteal protocol) was not significantly different. Although E₂ AUC in luteal protocol was higher than that in flare protocol, the difference was not statistically significant (28,339 ± 2,669 vs 26,905 ± 2,790). Differences in P and D₄ AUC between the two protocols were not statistically significant. Correlations with ovarian follicles and eggs retrieved were better for AMH than E₂. Conclusions: The luteal protocol exhibited a better ovarian response to stimulation as compared to the flare protocol. As compared to E₂, AMH had a better correlation with the number of follicles and eggs retrieved.

Denna studie utgår från den Adaptiva marknadshypotesen som genom ett evolutionärt perspektiv sammanbinder de två grundparadigmen Effektiva marknadshypotesen och Finansiell beteendevetenskap i ett försök att föra forskningen om marknadseffektivitet framåt. Vidare undersöker studien den svenska aktiemarknaden på ett, för den Adaptiva marknadshypotesen, nytt sätt där marknadseffektivitetens dynamik inom marknaden kartläggs och analyseras. Undersökningsenheterna består av OMX Stockholm All Share Index samt aktiemarknadens, utifrån marknadskapitalisering, fem största sektorindex. Med en robust metodologi kartlägger vi effektivitetsdynamiken mellan prisserierna under åren 2000-2013 och finner stöd för den adaptiva marknadshypotesens förmenanden utifrån såväl marknadsindex som majoriteten av undersökta sektorindex. Studien påvisar också att effektivitetsanalys utifrån marknadens beståndsdelar åskådliggör effektivitetsdynamik inom marknaden, på ett sätt som analys av endast marknadsindex missar. Kartläggning utifrån sektorer visar även att förändringar i marknadsmiljön kan ge upphov till adaptiva ineffektiviteter på isolerade marknadssegment, och erbjuder därmed utveckling av AMH som i sin nuvarande form endast beaktar homogen förmåga för marknaden att bearbeta och inkorporera förändringar. Detta belyser betydelsen av diversifiering med avseende på effektivitet vid investeringsbeslut. Riskindikatorer för ineffektiviteter i respektive sektor samt korrelationsmatris över sektorers samvarierande effektivitet tas därför fram som initiala beslutsunderlag och komplement till traditionell portföljvalsteori. Ända sedan den effektiva marknadshypotesen formulerades av Eugene F. Fama för snart ett halvt sekel sedan har marknadseffektivitet debatterats kraftigt inom den finansiella forskningen. Den adaptiva marknadshypotesen erbjuder en ytterst tilltalande förklaring till marknadens beteende, där konsolidering mellan förespråkare för EMH och finansiell beteendevetenskap möjliggörs. Teorins potential att föra fundamental finansforskningen framåt har därför gjort att AMH, trots sin ringa ålder, snabbt fått uppmärksamhet inom forskningsdiskursen, och det är också av dessa anledningar vi sökt testa och samtidigt utveckla teorin och dess implikationer i en svensk kontext.

Background: Due to the “flare effect” associated with the flare protocol, variation in the degree of follicular maturation during stimulation may result in differences in follicle response as compared to the luteal protocol which is based on maximal pituitary suppression and synchronization of follicular maturation. In this study, besides other methods, Anti-Mullerian Hormone (AMH), a novel marker for ovarian reserve, was used as a tool to evaluate the ovarian responsiveness to stimulation. Methods: Women undergoing IVF/ICSI treatment in the UBC IVF Program from January to December 2006 using luteal and flare protocols were retrospectively selected for a total of 40 treatment cycles, 20 cycles in each protocol matched by age, weight, and indication for IVF/ICSI. Serial serum Estradiol (E₂) levels and follicle data were obtained from the clinic chart. Follicle stimulating hormone (FSH), Luteinizing Hormone (LH), progesterone (P), androstenedione (D₄) and AMH levels were measured from aliquots of frozen serum samples. Hormone responses were evaluated by Area Under the Curve (AUC). Data were analyzed using the t-test and statistical significance was considered present at P<0.05. Results are reported as the mean ± SEM. Results: For flare versus luteal protocol, there was a significant difference in the number of total follicles (14.5 ± 1.8 vs 21.3 ± 2.3), medium follicles (3.7 ± 0.6 vs 8.4 ± 1.3), eggs retrieved (8 ± 0.8 vs 14 ± 1.4) and oocytes fertilized (4.4 ± 0.5 vs 8.4 ± 0.7), AMH AUC (62 ± 12 vs 111 ± 13), LH AUC (67 ± 21 vs 20 ± 9), FSH AUC (171 ± 59 vs 112 ± 29), respectively. Mean number of embryos transferred in both groups was similar. Number of pregnancies conceived (5 for flare and 10 for luteal protocol) was not significantly different. Although E₂ AUC in luteal protocol was higher than that in flare protocol, the difference was not statistically significant (28,339 ± 2,669 vs 26,905 ± 2,790). Differences in P and D₄ AUC between the two protocols were not statistically significant. Correlations with ovarian follicles and eggs retrieved were better for AMH than E₂. Conclusions: The luteal protocol exhibited a better ovarian response to stimulation as compared to the flare protocol. As compared to E₂, AMH had a better correlation with the number of follicles and eggs retrieved.

Background: Due to the “flare effect” associated with the flare protocol, variation in the degree of follicular maturation during stimulation may result in differences in follicle response as compared to the luteal protocol which is based on maximal pituitary suppression and synchronization of follicular maturation. In this study, besides other methods, Anti-Mullerian Hormone (AMH), a novel marker for ovarian reserve, was used as a tool to evaluate the ovarian responsiveness to stimulation. Methods: Women undergoing IVF/ICSI treatment in the UBC IVF Program from January to December 2006 using luteal and flare protocols were retrospectively selected for a total of 40 treatment cycles, 20 cycles in each protocol matched by age, weight, and indication for IVF/ICSI. Serial serum Estradiol (E₂) levels and follicle data were obtained from the clinic chart. Follicle stimulating hormone (FSH), Luteinizing Hormone (LH), progesterone (P), androstenedione (D₄) and AMH levels were measured from aliquots of frozen serum samples. Hormone responses were evaluated by Area Under the Curve (AUC). Data were analyzed using the t-test and statistical significance was considered present at P<0.05. Results are reported as the mean ± SEM. Results: For flare versus luteal protocol, there was a significant difference in the number of total follicles (14.5 ± 1.8 vs 21.3 ± 2.3), medium follicles (3.7 ± 0.6 vs 8.4 ± 1.3), eggs retrieved (8 ± 0.8 vs 14 ± 1.4) and oocytes fertilized (4.4 ± 0.5 vs 8.4 ± 0.7), AMH AUC (62 ± 12 vs 111 ± 13), LH AUC (67 ± 21 vs 20 ± 9), FSH AUC (171 ± 59 vs 112 ± 29), respectively. Mean number of embryos transferred in both groups was similar. Number of pregnancies conceived (5 for flare and 10 for luteal protocol) was not significantly different. Although E₂ AUC in luteal protocol was higher than that in flare protocol, the difference was not statistically significant (28,339 ± 2,669 vs 26,905 ± 2,790). Differences in P and D₄ AUC between the two protocols were not statistically significant. Correlations with ovarian follicles and eggs retrieved were better for AMH than E₂. Conclusions: The luteal protocol exhibited a better ovarian response to stimulation as compared to the flare protocol. As compared to E₂, AMH had a better correlation with the number of follicles and eggs retrieved. / Medicine, Faculty of / Obstetrics and Gynaecology, Department of / Graduate

Introdução: O processo de envelhecimento reprodutivo ocorre em virtude do declínio progressivo na quantidade e qualidade de óvulos que se inicia após a puberdade, se mantém ao longo da menacme, com redução gradual da fertilidade, e termina na menopausa, caracterizada pelo esgotamento do número de folículos e, consequentemente, da reserva ovariana funcional (ROF). A vida pré-natal constitui um importante período para o desenvolvimento dos órgãos genitais internos femininos e mudanças nessa fase podem ter repercussões futuras: quando o feto é submetido a condições adversas intrauterinas, mecanismos metabólicos e endócrinos de adaptação podem mudar o eixo metabólico pós-natal predispondo a certas doenças na vida adulta. Com base nesses dados, postulou-se que condições desfavoráveis de vida intrauterina que poderiam se refletir com alterações do peso ao nascer (PN) poderiam levar à reprogramação de genes envolvidos no controle da ROF e que talvez nascer pequeno para idade gestacional (PIG) ou grande (GIG) possibilitaria a interferência com a ROF estimada por meio das concentrações séricas do hormônio antimülleriano (AMH). Objetivos: O objetivo deste estudo foi avaliar a relação do PN com a ROF, estimada por meio da concentração sérica do AMH em mulheres na menacme com 34 a 35 anos de idade. Pacientes e Métodos: Trata-se de um estudo transversal aninhado a uma coorte de mulheres que nasceram no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), no período de 01 de junho de 1978 e 31 de maio de 1979. O desfecho primário avaliado foi a concentração sérica de AMH, um marcador da ROF, e sua correlação com o PN, divididos em três grupos: PIG, adequado para a idade gestacional (AIG) e GIG. Resultados: Das 274 pacientes incluídas no estudo, 19 foram classificadas como PIG, 238 como AIG e 17 como GIG. As concentrações médias de AMH não foram significativamente diferentes (p=0,11) entre mulheres na menacme nascidas PIG, AIG e GIG (2,14 ng/mL, 2,13 ng/mLe 2,57 ng/mL, respectivamente). Conclusão: Não se observou diferença nas concentrações séricas de AMH entre mulheres nascidas PIG, AIG e GIG avaliadas entre 34 e 35 anos de idade. A casuística avaliada permitiu detectar ou descartar uma grande diferença entre os grupos (effectsize de 0,7). Dessa forma, evidenciou-se que o PN não apresenta grande influência sobre a ROF, estimada pelas concentrações séricas do AMH, em mulheres na menacme, entre 34 e 35 anos de idade. Caso novos estudos evidenciem que diferenças pequenas ou moderadas nas concentrações séricas do AMH possam apresentar relevantes repercussões clínicas em mulheres nesta faixa etária, outras pesquisas serão necessárias, sendo os dados do presente estudo úteis para o cálculo amostral. / Background: The reproductive aging process occurs by a progressive decline in the quantity and quality of oocyte, starting after pubertal onset, remaining through menacme with gradual reduction of fertility and ends with menopause, which is the depletion of ovarian follicles and hence the depletion of functional ovarian reserve (FOR). Prenatal life corresponds to a critical window for the development of female internal genitalia and changes at this stage may have future repercussions: when the fetus is submitted to intra uterine adverse conditions, adaptive metabolic and endocrine mechanisms will change the metabolic axis in the postnatal period thereafter predisposing to several diseases in adulthood. Based on this correlation, we postulate that unfavorable conditions of intrauterine life that could reflect on birth weight (BW) could lead to the reprogramming of genes involved in the control of FOR and that maybe being born small for gestational age (SGA) or large for gestational age (LGA) could interfere with the FOR estimated through serum concentrations of Anti-Müllerian hormone (AMH). Objective: To investigate the relationship between BW and ROF estimated through AMH serum concentration in menacme women with 34-35 years old. Patients and Methods: This is a prospective birth cohort assessing all women who were born in Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP) between June 1, 1978 and May 31, 1979. The primary endpoint was to evaluate serum AMH concentration, a marker of FOR and its correlation with BW divided into three groups: SGA, adequate for gestational age (AGA) and LGA. Results: Out of the 274 patients included in the study: 19 were classified as SGA, 238 as AGA, and 17 as LGA. The average of AMH concentrationwas not significantly different (p=0.11) among women in reproductive age born SGA, AGA and LGA (2.14 ng/mL, 2.13 ng/mL, and 2.57 ng/mL respectively. A variance analysis between the three groups and OR did not find a significant different between them (p=0.11). Conclusion: There was no difference in serum AMH concentration in women born SGA, AGA and LGA with 34 to 35 years old. This sample also allowed to detect or rule out a major difference between the groups (effect size of 0.7). In conclusion, BW does not have a great influence on FOR, estimated through serum AMH concentration in menacmewomen, between 34 and 35 years old. If new studies show clearly that small or moderate differences in serum AMH concentration could impact clinical outcomes in women at this age, further studies will be needed, and the data of this study could be useful for sample size calculation.

Chez la vache le développement des techniques d’induction d’ovulations multiples et de production d’embryons est limité par la variabilité inter-individuelle de la réponse ovarienne au traitement de superovulation. Chez la femme, l’Hormone anti-Müllérienne (AMH) est le meilleur marqueur endocrinien de la réponse folliculaire au traitement de stimulation ovarienne. Les objectifs de mon travail étaient d’étudier l’AMH comme marqueur endocrinien de la réponse ovarienne à un traitement gonadotrope chez la vache et d’étudier la régulation de la production d’AMH par les cellules de granulosa. Nos résultats montrent que les concentrations plasmatiques d’AMH sont prédictives de la réponse ovulatoire à un traitement gonadotrope. Au cours du cycle, les concentrations d’AMH ont un profil en 2 temps : elles diminuent entre les chaleurs et J5 à J8, puis augmentent jusqu’aux chaleurs suivantes. Pour prédire efficacement la réponse ovulatoire, les concentrations d’AMH doivent être mesurées aux chaleurs ou après J12 du cycle. L’étude de la régulation de la production in vitro d’AMH par les cellules de granulosa montre que BMP stimule tandis que FSH inhibe la production d’AMH. / In the cow, the development of multiple ovulation and embryo transfer technologies is limited by the variability between animals in ovarian responses to superovulatory treatments. In the women, the anti-Mullerian Hormone (AMH) is the best marker of follicular response to a stimulatory treatment. The objectives of my work were to study AMH as an endocrine marker of the ovulatory response to a stimulatory treatment in the cow and to study the regulation of AMH production by granulosa cells. Our results show that plasma AMH concentrations can predict the ovulatory responses to a stimulatory treatment. During the estrous cycle, AMH concentrations have a dynamic profile in 2 steps: AMH concentrations decrease between estrus and D5 to D8 and then they increase until the next estrus. To predict in optimal conditions, AMH has to be measured at the estrus time or after D12 of the estrous cycle. In vitro, the study about regulation of AMH production by granulosa cells indicates that BMP enhances whereas FSH decreases AMH production.

La compréhension de la régulation de l’AMH et de son récepteur spécifique, l’AMHR2, par les BMPs a amené un éclairage nouveau sur leur rôle dans le développement folliculaire et la régulation du taux d’ovulation. Nos résultats se basent sur l’étude de 4 modèles ovins porteurs de mutations Fec, mutations qui affectent des membres de la famille des BMPs, à savoir leur ligand BMP15 ou leur récepteur. Ces mutations se traduisent phénotypiquement par une baisse de l’expression de l’AMH ou de son récepteur dans les cellules folliculaires, et des ovulations multiples chez les brebis porteuses. D’un point de vue mécanistique, nos résultats ont mis en évidence une régulation de l’AMH et de l’AMHR2 par les BMPs in vivo et in vitro, passant par le récepteur BMPR1B, et s’exerçant sur l’activité transcriptionnelle du promoteur de l’AMH via SMAD1 et SF1. Cette régulation a également été en partie mise en évidence dans l’espèce porcine avec une observation supplémentaire dans ce modèle : un taux d’ovulation naturellement très élevé est associé à une faible production ovarienne d’AMH. Ces observations mettent en exergue le rôle possible de l’AMH dans la régulation du taux d’ovulation. / The understanding of the regulation of AMH and its specific receptor, AMHR2, by the BMPs, brought a new highlight on their role in the regulation of follicular development and the control of ovulation rate. Our results are based on the study of 4 sheep models carrying Fec mutations which affect different members of the BMPs family, namely their ligand BMP15 or their receptor, Mutations result phenotypically in a low expression of AMH or AMHR2 in the granulosa cells of ovarian follicles, and multiple ovulations in carrier ewes.. From a mechanistic point of view, the results demonstrated the in vivo and in vitro regulation of AMH and AMHR2 by BMPs, acting through the BMPR1B receptor and enhancing the transcriptional activity of the AMH promoter via SMAD1 and SF1. This regulation has also been partially demonstrated in swine with an additional observation in this model: a naturally high ovulation rate is associated with a low ovarian production of AMH. In conclusion, these observations show a possible role of the AMH in the regulation of ovulation rate.