Klinische Forschung der Klinik für Reproduktions-Endokrinologie

Entwicklung eines mathematischen Modells des weiblichen Zyklus sowie zur Unterstützung von Kinderwunschbehandlungen

Summary

Infertilität betrifft 12% – 15% der Paare im reproduktionsfähigen Alter in Europa und führt allein in Europa zu Kosten von ungefähr einer Billionen Euro pro Jahr. Experten gehen von einer Verdopplung dieser Kosten in der nächsten Dekade aus. Bei ca. 50% der betroffenen Paare basiert die Infertilität auf gesundheitlichen Störungen der Frau, mehr als 40% dieser Störungen sind endokrinologisch bedingt. Diese Störungen können neben den Auswirkungen auf die Fertilität zu weiteren langfristigen gesundheitlichen Einschränkungen z.B. kardiovaskulären Erkrankungen führen. Um diese Situation zu verbessern, wurde unser auf drei Säulen basierendes Forschungsprojekt zur Entwicklung eines mathematischen Modells für Infertilitäts-assoziierte endokrinologische Störungen.

Studiendesign

Erhebung klinischer und laborchemischer Daten, welche etappenweise in ein biologisch basiertes mathematisches Gundmodell eingefügt werden. Dieses Modell wird mittels – in anderen Zusammenhängen (Weltraumforschung) genutzten Ansätzen aus der Informatik – auf Stabilität geprüft und mit jeder Serie von Datensätzen verbessert und verfeinert.
Serielle Blutproben über ein bis zwei Menstruationszyklen von verschiedenen Gruppen von Frauen mit normalen bzw. auffälligen Menstruationszyklen werden für die Differenzierung des Modells genutzt. Dabei werden von folgenden Gruppen endomrinologische Parameter evaluiert:

1. Gesunden Frauen mit normalem (nl) Zyklus,
2. Raucherinnen mit nl Zyklus,
3. Adipösen Frauen mit nl Zyklus,
4. Frauen mit Endometriose und nl Zyklus,
5. Frauen mit Oligomenorrhoe bei PCOS,
6. Untergruppe von gesunden Frauen mit nl Zyklus mit zusätzlichen Blutentnahmen nach Geschlechtsverkehr.

Das auf dieser Basis entwickelte Zyklusmodell wird in Bezug auf die Vorhersage der Stimulationsphase von Kinderwunschbehandlungen weiterentwickelt. Erste Schwerpunkte sind:

1. Infertile Frauen ohne endokrinologische Störung (Kurzprotokoll)
2. Infertile Frauen ohne endokrinologische Störung (Langprotokoll)
3. Infertile Frauen mit Endometriose (Kurz- oder Langprotokoll)
4. Infertile Frauen mit PCOS (Langprotokoll)

Studienablauf (Untersuchungen studienspezifisch/-unspezifisch)
Bis sieben Blutentnahmen/Zyklus über ein bis zwei Menstruationszyklen
Intensivierte (= acht zusätzliche) Messungen nach Geschlechtsverkehr, drei Mal während des Menstruationszyklus in einer Untergruppe von 12-15 Frauen

Ausserdem Auswertung von Daten, welche routinemässig während Kinderwunschbehandlungen erhoben werden.

Key words / Suchbegriffe

Menstrual cycle, PCOS, fertility treatment

Project leadership and contacts / Projektleiter

Prof. Dr. med. Brigitte Leeners

In cooperation with / Kooperationspartner

• Prof. Dr. med. Enrico Tronci, Computer science, University Sapienza Rome
• Prof. Dr. med. Susanna Röblitz, ZUSE Institute, Berlin
• PD Dr. med. Marcel Egli, University Luzern, Space biology group
• Prof. Dr. med. Tillmann Krüger, Medical School Hannover, Psychiatry, Social Psychiatry and Psychotherapy

Funding sources and project duration

EU: Feb 2013 – Dec 2016

Summary

Throughout the menstrual cycle we conduct four measurements (early follicular, pre-ovulatory, mid-luteal and pre-menstrual) of neurocognitive performance. A computer assisted neurocognitive test-battery (CANDIT) is used to evaluate correlation between different hormonal constellations and different neuropsychological parameters. Tests focus on attention, concentration, learning and memory, stress regulation, social comprehension, regulation of emotions, reactions to sexual stimuli as well as food cravings.

Key words / Suchbegriffe

hormones, cycle, neurocognitive performance, sexual stimuli

Project leadership and contacts / Projektleiter

Prof. Dr. med. Brigitte Leeners

In cooperation with / Kooperationspartner

• PAEON – Consortium
• Prof. Dr. Guy Bodenmann

Funding Sources and project duration

Gottfried and Julia Bangerter-Rhyner Stiftung: Mar 2014 – Dec 2020

Summary

Adipositas ist eine weltweit zunehmende Epidemie mit schwerwiegenden gesundheitlichen Folgeerscheinungen wie Herz-Kreislauf-Erkrankungen und Diabetes Typ 2. Übermässiges Essen ist eine der Hauptursachen dieser Entwicklung. Frühere Studien an Tieren und Menschen deuten darauf hin, dass Fortpflanzungshormone an der Regulation des normalen und gestörten Essverhaltens sowie des Körpergewichts beteiligt sind. Dies zeigt auch die höhere Prävalenz der Adipositas bei Frauen gegenüber Männern in den USA, der Schweiz und weiteren Ländern. Ein besseres Verständnis der hormonellen Einflüsse auf die zentrale neuronale Regulation des Essverhaltens, die Ausschüttung gastrointestinaler Verdauungshormone, die Essensportionsgrössen und die Gelüste auf spezielle Nahrungsmittel, bietet die Möglichkeit die bestehenden, derzeit recht unbefriedigenden therapeutischen Optionen zur Reduktion einer Adipositas erweitern.

Sättigung ist ein Prozess im Gehirn, welcher dazu führt, dass eine Mahlzeit beendet wird, wobei die aufgenommene Nahrung einen reflexartigen negativen Rückkopplungsmechanismus auslöst. Dieser Mechanismus wird stark durch unterschiedliche Essensgelüste, aktuelle soziale Rahmenbedingungen und den persönlichen Bezug zum Essen beeinflusst. Neben dem akuten Ess-verhalten bestimmen längerfristige subjektive Parameter und sozio-kulturelle Faktoren die Mahlzeitengrösse und die Gesamtnahrungsaufnahme.

Die vorliegende Studie untersucht den Zusammenhang zwischen Steroidhormonen, gastrointestinalen Peptidhormonen und der Sättigungsaktivität im Gehirn. Frühere funktionelle Magnetresonanztomographie (fMRT) Studien geben erste Einblicke in zentrale Aktivierungsmuster, andere Studien in Sättigungseffekte von Cholecystokinin (CCK) und Glucagon-like Peptid 1 (GLP-1), welche in dem vorliegenden Projekt parallel untersucht werden.

Key words / Suchbegriffe

adipositas, estrogen, progesterone, fMRI, CCK, GLP-1

Project leadership and contacts / Projektleiter

• Prof. Dr. med. Brigitte Leeners
• Dr. Lori Asarian
• Prof. Dr. Philippe Tobler

Funding Sources and project duration

Forschungskredit der Universität Zürich: Jul 2014 – Dec 2020

Publications

Egli M*, Leeners B*, Kruger TH (2010) Prolactin secretion patterns: basic mechanisms and clinical implications for reproduction. Reproduction, 140(5):643-54

Summary

Research results suggest changes of various physiological parameters during the menstrual cycle. The present study aims to evaluate whether there is a correlation between physiological parameters and the menstrual cycle i.e. ovulation as measured by a urine ovulation test and the onset of menses. We are currently in the process of validating a promising solution.

Key words / Suchbegriffe

menstrual cycle, physiological changes

Project leadership and contacts / Projektleiter

Prof. Dr. med. Brigitte Leeners

In cooperation with / Kooperationspartner

• Jens Kraus, CSEM, Switzerland
• Simon Annaheim, EMPA (Swiss Federal Laboratories for Materials Science and Technology), Switzerland
• Pascal Koenig, AVA AG, Switzerland

Funding Sources and project duration

KTI: Oct 2014 – Oct 2016

Summary

Current therapeutic options allow successful treatment in only part of the women presenting with endometriosis. Pain, fatigue/exhaustion, intensive and repeated therapies as well as a concentration on the disease lead to a variety of consequences on education/profession, body perception, self-esteem, partnership/social contacts, sexuality and psychic well-being.
However, scientific data on this topic are sparse. The research projects aims to collect systematic data on different aspects of the quality of life in women with endometriosis compared to controls.

Women are recruited in different hospitals such as the university hospital Zürich, the Charité in Berlin, the University hospital Aachen, the University Hospital Graz as well as several district hospitals in Switzerland. The questionnaire is also distributed to women contacting the German and Swiss Self-help organisations for women with endometriosis. Any diagnosis is confirmed by the women’s medical charts.
The questionnaire includes questions on socio-demographic data, on life style, general, gynaecological and obstetrical history, specific questions on endometriosis, pain  (modified version of the BPI and PDI, resources (SOC), stress perception (PSQ20), professional career, satisfaction with medical support, childhood experiences (modified version of the CTQ), everyday life, partnership (PFB), sexuality (modified version of the Brief Index of Sexual Functioning and Global sexual functioning) and fearfulness/depression (PHQ, GAD). Socio-demographic questions, questions on the partnership as well as on effects of endometriosis on the partnership are also addressed to partners.

A total of > 500 matched pairs (matched for age) will be evaluated.

Key words / Suchbegriffe

Endometriosis, quality of life, endometriosis-associated pain, sexuality, childhood experiences

Project leadership and contacts / Projektleiter

Prof. Dr. med. Brigitte Leeners

In cooperation with / Kooperationspartner

Different hospitals as mentioned above

Funding Sources and project duration

No project-specific funding: Jan 2008 – Dec 2020

Summary

Our previous pilot study demonstrated a positive impact of desogestrel on migriane frequency and intensity. These findings are planned to be further investigated with in a prospective study.

Key words / Suchbegriffe

migrine desogestrel

Project leadership and contacts / Projektleiter

PD Dr. med. Gabriele S. Merki-Feld

Funding Sources and project duration

No project-specific funding: Apr 2013 – Apr 2016

Summary

Neuroendocrine mechanisms in human reproduction:
The pituitary hormone prolactin (PRL) is one of the most versatile hormones of mammalian organisms and affects many physiological processes. It plays a major role in mammary gland development, initiation and maintenance of lactation as well as in reproduction. PRL also contributes to immune modulation, osmoregulation, and sexual behavior. Although PRL animal knock-out studies clearly indicate that this hormone is necessary for normal fertility, controversial data are available in the literature about the importance of PRL in human gestation and no concluding opinion has established yet. The goal of our study is to further elucidate the regulation of human PRL in relation to the menstrual cycle. These data will later serve to gain insights in the involvement of PRL secretion patterns in early pregnancy and sterility problems.

We have been investigating the PRL secretion controlling network in rodents for the past years, leading to the identification of a core neuronal network that seems to be responsible to control the secretory pattern under various physiological situations. In addition, we designed mathematical models based on the experimental data, which illustrates the interplay of releasing/inhibiting factors necessary to generate the observed PRL secretory pattern in normal cycling rats as well as in pregnant/pseudopregnant rats. Surprisingly, all the core elements of the rat neuronal network that we believe are necessary to control various PRL secretory patterns can also be found in humans and studies have shown that the animal and the human neuronal networks share similar basic features.

We are proposing to investigate the secretory response of several hormones to sexual activity in humans during a 48-hour period. Following the activity, serial blood samples will be taken frequently in order to be able to detect even transient secretory peaks. Results from the blood sample analysis will allow us to draw a circadian secretory pattern of the investigated hormones and thus to elucidate whether changes occurred after sexual activity and may therefore have a significant contribution to successful reproduction. In addition, the obtained data will also be incorporated into our existing mathematical model to further analyze the secretory rhythms and to illustrate the interplay of stimulatory as well as inhibitory factors that control PRL secretion.

The combination of endocrinology and mathematical modelling is a new and innovative approach in the field of medicine. Only a few studies have been published so far which have used similar methods. Mathematical models are useful tools to illustrate complex mechanisms within neuronal networks controlling hormone secretion, like the PRL neurosecretory network. In the future, computer simulations of human endocrine mechanisms could even be used as a diagnostic tool or as an alternative way optimizing treatments. We anticipate that our joint experimental / modelling will motivate others to introduce modelling and computer simulations into their investigations of the hypothalamic control of hormone secretion.

Key words / Suchbegriffe

prolactin, sexual contact, regulation, oxytocin

Publications

Egli M*, Leeners B*, Kruger TH (2010) Prolactin secretion patterns: basic mechanisms and clinical implications for reproduction. Reproduction, 140(5):643-54

Project leadership and contacts / Projektleiter

• Prof. Dr. med. Brigitte Leeners
• Dr. Marcel Egli
• Prof. Dr. Tillmann Krüger

In cooperation with / Kooperationspartner

• Dr. Marcel Egli, Space Biology Group and Biotechnology Space Support Center, Earth Science, ETH Zürich, Switzerland
• Prof. Dr. Tillmann Krüger, Klinik für Psychiatrie, Universität Hannover, Germany

Funding Sources and project duration

Foundation: Aug 2007 – Dec 2015

Summary

Cardiovascular diseases are strongly influenced by stress and have many risk factors in common with hypertensive diseases in pregnancy. As prophylactic therapeutic options against hypertensive diseases in pregnancy are needed urgently, we investigated the correlation between these diseases and psychosomatic as well as endocrinological factors before and during pregnancy.

A questionnaire comprising obstetrical and psychosocial questions was sent to 2,600 women with hypertensive disorders during pregnancy and to 1,233 control women. After matching for age, parity, nationality, and educational level, depending on the aspect investigated between 726 and 1067 patients as well as 880 to 1063  controls were evaluated.

Key words / Suchbegriffe

hypertensive diseases in pregnancy, pre-eclampsia, HELLP-syndrome, BMI, stress, family, breast feeding, information, smoking, BMI, weight

Project leadership and contacts / Projektleiter

Prof. Dr. med. Brigitte Leeners

In cooperation with / Kooperationspartner

• Prof. Dr. Werner Rath, Dept. of Gynecology and Obstetrics, University Hospital Aachen, Germany
• Gestosefrauen e.V. (Selbsthilfegruppe für betroffene Frauen), Issum, Germany

Funding Sources and project duration

EU and Other Public Sources (e.g. Federal or Cantonal Agencies): Mar 1999 – Dec 2015

Publications

• Leeners B., W. Rath, S. Kuse, P. Neumaier-Wagner: Breast-feeding in women with hypertensive disorders in pregnancy, J Perinatal Med 33 (6): 553-60, 2005
• Leeners B., Neumaier-Wagner P., Kuse S., Neises M., Rath W.: Satisfaction with medical information in women with hypertensive disorders in pregnancy; J Psychosom Res, 60 (1):39-44, 2006
• Leeners B., W. Rath, S. Kuse, C. Irawan, P. Neumaier-Wagner: The significance of under- or overweight during childhood as a risk factor for hypertensive diseases in pregnancy, Early Hum Dev, 2006; 82 (10):663-668
• Leeners B., P. Neumaier-Wagner, S. Kuse, C. Irawan, B. Imthurn, W. Rath: Family stability during childhood and the risk to develop hypertensive diseases in pregnancy, Early Hum Dev, 2006; 82(7):441-446
• Leeners B., Rath W., S. Kuse, C. Irawan, B. Imthurn, P. Neumaier-Wagner: Pre-pregnancy BMI: New aspects of a classical risk factor for hypertensive disorders in pregnancy, Clin Science, 2006; 111:81-86
• Leeners B., Neumaier-Wagner P., Kuse S., Rath W.: Smoking and the risk of developing hypertensive diseases in pregnancy – what is the effect on HELLP syndrome?; Acta Obstet Gynecol Scand. 2006; 85 (10):1217-1224
• Leeners B., Neumaier-Wagner P., Sabine Kuse S., Stiller R., Rath W.: Emotional stress and the risk to develop hypertensive diseases in pregnancy, Hypertens Preg, accepted

Summary

In different in vitro studies the role and eventual therapeutic potential of different estrogen metabolites is evaluated. To gain insight in underlying pathophysiological mechanisms experiments are conducted while different receptors are blocked. Also estrogen effects on different regulatory processes of the cell cycle are investigated.

Key words / Suchbegriffe

Estrogen metabolites, hydroxyestradiol, methoxyestradiol

Project leadership and contacts / Projektleiter

Prof. Dr. med. Brigitte Leeners

In cooperation with / Kooperationspartner

Prof. Dr. sc. nat. Raghvendra Dubey

Funding Sources and project duration

Foundation: Feb 2005 – Apr 2016