Gynaecological Endocrinology and Reproductive Medicine

302089, 302033

early pregnancy, endometriosis, fertility preservation, gender identity disorders, gynaecological endocrinology, PCOS, recurrent implantation failure, recurrent miscarriage, reproductive immunology, and Reproductive medicine

Our research focuses on the physiology and pathology of ovarian and uterine function as well as reproductive immunology, with the following main topics:

Early and recurrent pregnancy loss as well as recurrent implantation failure
Immune tolerance and implantation
Fertility preservation
Endometriosis
Gynaecological endocrine disorders
Contraception

Disturbances of gender identity

The research unit is structured around the laboratories located at the Innrain interdisciplinary facility and at the clinical unit of Gynaecological Endocrinology and Reproductive Medicine. We perform translational research with the aim of applying results obtained in the laboratory to the clinical care of patients and we undertake ongoing clinical research studies. Our clinical outpatient services have more than 17,000 annual patient contacts for endocrine and fertility-related disorders. The department is the coordinating site of the SEF/EEL-certified clinical-research endometriosis centre, the fertility preservation centre of the FertiProtekt Network and the hormonal centre of Transgender Center Innsbruck (TGCI). We perform over 500 stimulated and natural-cycle IVF/ICSI cycles and more than 350 frozen embryo transfers per year. In addition, we offer oocyte, sperm, embryo and ovarian tissue cryopreservation for patients facing loss of fertility as a result of autoimmune and malignant diseases. The IVF laboratory routinely performs embryo culture and cryopreservation as well as trophectoderm biopsies for pre-implantation genetic testing and works hand-in-hand with our research unit. We collaborate with a number of clinical and scientific units of the Medical University of Innsbruck as well as international research partners. Furthermore, we participate in the fellowship programme sponsored by the European Society of Human Reproduction and Embryology (ESHRE), for subspecialty training in reproductive medicine. Multiple members of our department coordinate and serve on international practice guideline committees and are members of academic journal editorial boards. In 2022, Professor Toth was elected to a three-year term as President of the Austrian College of Gynecology and Obstetrics.

Role of Dendritic Cells in Immune Tolerance and Early Implantation Failure

Ch. Kyvelidou, B. Toth, S. Tollinger

Dendritic cells (DC) are critical immune cells at the heart of the delicate balance that allows embryo implantation and the establishment of immune tolerance towards the developing foetus. Therefore, disruption of their normal function could lead to complications, such as implantation failure or early pregnancy loss. We hypothesise that DC in the female reproductive tract can assist or hinder embryo implantation depending on signalling molecules they receive from the pre-implantation embryos themselves. Subsequently, these DC will interact with other immune cell populations, such as T cells and natural killer (NK) cells, creating either a favourable or a disadvantageous immune environment at the implantation site.

To test this, we are collecting spent media (SM) of good quality human pre-implantation embryos that either have or have not been successfully implanted and use them to stimulate monocyte-derived DC in vitro.

Our results so far indicate that human pre-implantation embryos secrete cytokines and chemokines in vitro that affect moDC cells. Specifically, moDC stimulated with SM from implanted embryos were less activated than moDC stimulated with SM from non-implanted embryos. Moreover, depending on the SM used, moDC affected T cell memory differentiation and activation, but not T cell proliferation.

These findings indicate that pre-implantation embryos have the ability to affect the maternal immune system and actively influence their fate.

Recurrent Pregnancy Loss, Recurrent Implantation Failure

B.Toth, AS. Braun, H., C.Kyvelidou

Our group focuses on the identification of novel risk factors for recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) since the aetiology of these problems remains elusive in approximately 50% of affected patients. We aim to identify new immunological risk factors in patients with RM and RIF, by focusing on lymphocyte subpopulations such as Treg, dendritic and NK-cells and on their interaction with the feto-maternal interphase, as well as the uterine microbiome. By analysing immunological risk factors before conception and during (early) pregnancy, we aim to elucidate the roles of the different immunological factors in RPL and RIF, with the objective of identifying future immunomodulatory treatment-strategies. In our clinical studies, we correlate diagnostic factors and applied treatment strategies to pregnancy outcomes.

Early Pregnancy

B.Seeber, A.Zippl, H. Welponer

Pregnancies following IVF have been reported to have a higher risk of complications associated with placentation problems, including pre-eclampsia, premature delivery and babies that are small for their gestational age. We recently completed and published a clinical study that identified a high concentration of first-measured hCG following embryo transfer as a risk factor for developing pre-eclampsia. Ongoing studies aim at expanding and validating these findings.

In additional work in the field of early pregnancy, we evaluate the success rates of medical management in early pregnancy failure.

We recently published a retrospective clinical study to estimate pregnancy success rates of intrauterine insemination based on clinical parameters.

Endometriosis

B.Seeber, A. Zippl, E. Reiser, B. Böttcher

Our certified clinical and research Endometriosis Centre takes part in multi-centre international research studies evaluating the accuracy of non-invasive diagnosis and the outcomes of medical and surgical treatment, leading to several publications. We are the principal investigation centre for an ongoing multi-centre study correlating patients’ symptoms and quality of life to the localisation of endometriosis lesions. Further studies have evaluated the quality of life of affected couples.

Adenomyosis and immunological disorders

B.Seeber, A.Zippl, C.Kyvelidou, B. Toth

Our investigator-initiated projects evaluate embryo implantation problems in women with endometriosis and adenomyosis, focusing on immunological alterations. We investigate whether treatment with GnRH agonists prior to embryo transfer has a positive effect on lymphocyte subpopulations in the endometrium and peripheral of women with adenomyosis. Preliminary results to be presented at the World Congress of Endometriosis show a decrease in the percentage of CD8⁺T cells and an increase in DN T cells after GnRH-a therapy, both important mediators of reproductive immune tolerance . Further studies are ongoing.

Gynaecological Endocrinology

B.Böttcher, H.Hosa, B.Seeber, B.Toth

Our endocrinology outpatient clinics treat women with common hormonal disorders, especially polycystic ovary syndrome (PCOS) and other anovulation disorders, premature ovarian insufficiency and gynaecological disorders in children and adolescents. We have designed and are currently conducting a prospective cohort study analysing the correlation between hormonal contraceptives and depression. Additional research areas focus on the effects of hormonal contraceptives and hormone replacement therapy on specific aspects of health and quality of life.

Fertility Preservation

B.Böttcher, S.Tollinger, E.Reiser, M.Paulitsch, B.Toth

As a member of the FertiProtekt Network, our clinic offers possible fertility preservation strategies to women who are affected by cancer. These include GnRH analogues, cryopreservation of oocytes and/or embryos, and cryopreservation of ovarian tissue followed by auto-transplantation after finishing the oncological treatment. The department was the first centre in Austria to perform ovarian tissue cryopreservation and to report a live birth after transplantation.

Damage to mouse/human ovary by low dose radiation

E.Reiser, C.Kyvelidou, B. Böttcher, S. Tollinger, B. Toth

Fertility preservation in children and young women undergoing radiation remains an unmet clinical need with a lack of research evaluating radiation-induced ovarian damage, especially from low dose or stray radiation. We need a better understanding of the factors that regulate radiation-induced damage to the ovarian stroma cells, taking into account the radiation dose.

We are currently performing an in vivo project in mice to gain insights on the effects of low dose radiation on ovarian tissue, a project supported by a MUI Start grant. Thus far, we have irradiated 144 mice with doses between 0.5 and 4.5 Gy and sacrificed the animals between 6h and 5 weeks post irradiation. Using immunohistochemistry and FACS analyses, we measure changes in follicle and immune cell numbers, as well as markers of cell damage (apoptosis, oxidative stress, DNA damage).

We have observed that yH2AX staining escalates with increasing radiation dose.

In vitro culture of mouse and human ovarian tissue

S. Tollinger, E. Reiser C.Kyvelidou, B. Böttcher, B. Toth

To analyse mouse and human ovarian tissue in its 3D architecture over a period of several days, we are currently using a vibrating compresstome to establish an in vitro culture system for mouse and human ovarian tissue slices. This method maintains the normal anatomical interactions between follicles and stromal cells of the ovary. We have succeeded in cultivating mouse ovarian tissue slices for up to five days, as confirmed by viability staining of follicles with Neutral Red.

Transgender persons and non-binary persons

K.Feil, H.Hosa, B.Böttcher, B.Toth

Transgender (TG) individuals experience a discrepancy between their sex assigned at birth and their experienced gender. Our department offers gender affirming hormone therapy for adolescents and adults, namely transgender woman and girls, transgender men and boys, as well as non-binary persons. In collaboration with the Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, we developed and validated a questionnaire to determine health-related quality of life in transgender persons, which we recently published. We are currently expanding this questionnaire to patients undergoing gender affirming hormone treatment. We recently completed a study in collaboration with the above department, which focused on adverse childhood experiences (ACE) in transgender persons compared to cisgender persons. In the very near future, we expect to publish our findings that TG patients reported a significantly higher number of ACEs than cisgender patients with substantial differences as early as age five.

In cooperation with the lab for Cognitive Neuroscience, we are investigating the influence of transitioning on the processing of linguistically perceived emotion in transgender women. We are also investigating the effects of testosterone treatment on the vaginal microbiome in transgender men compared to pre- and postmenopausal women.

• Vomstein K, Reider S, Böttcher B, Watschinger C, Kyvelidou C, Tilg H, Moschen AR, Toth B. Uterine microbiota plasticity during the menstrual cycle: Differences between healthy controls and patients with recurrent miscarriage or implantation failure. J Reprod Immunol. 2022 Jun;151:103634. doi: 10.1016/j.jri.2022.103634. Epub 2022 May 9.PMID: 35550495
• Feil K, Riedl D, Gschwentner L, Vomstein K, Wegscheider J, Arnold E, Toth B. Development of a quality of life questionnaire for transgender individuals during hormone therapy (iTransQol). Arch Gynecol Obstet. 2022 Oct;306(4):1337-1347. doi: 10.1007/s00404-022-06689-9. Epub 2022 Jul 25.PMID: 35876907 Shared first author+ Author
• Reiser, E.; Bazzano, M.V.; Solano, M.E.; Haybaeck, J.; Schatz, C.; Mangesius, J.; Ganswindt, U.; Toth, B. Unlaid Eggs: Ovarian Damage after Low-Dose Radiation. Cells 2022, 11, 1219. https://doi.org/10.3390/ cells11071219
• Zippl AL, Wachter A, Rockenschaub P, Toth B, Seeber B. (2022): Predicting success of intrauterine insemination using a clinically based scoring system. Arch Gynecol Obstet. 306(5):1777-1786.
• Aulitzky A, Lanbach J, Falkensteiner S, Maier S, Ulmer H, Toth B, Seeber B. (2022): High concentration of first-measured HCG after embryo transfer is associated with subsequent development of pre-eclampsia. Reprod Biomed Online. Oct 17:S1472-6483(22)00759-3. Epub ahead of print.

• FWF P 33249-B (S.Tollinger): Humanes Embryokulturmedium und dendritische Zellen
• Medizinischer Forschungsfonds Tirol (MFF) (A.L. Zippl): Impact of GnRH agonist treatment on immune cell populations in women with adenomyosis
• MUI Start (E. Reiser) : Fertility Protection: Understanding the cellular and molecular mechanisms that underlie radiation-induced ovarian damage
• MSD-Förderpreis (H.Hosa) zur Aufklärung über Humane Papillomaviren

Industry- and External grant-sponsored clinical studies

• OASIS: Phase-III-Study (Bayer AG) evaluating the efficacy and safety of elinzanetant for the treatment of vasomotor symptoms in menopause.
• BECONTRA Study (European Research Council to Belinda Petzer/University of Salzburg) evaluating the effects of birth control pills on the brain, especially during adolescence

• Doz. Dr. Emilia Solano, Laboratory for Translational Perinatology- Focus: Immunology, Chair of Obstetrics and Gynecology, focus: Obstetrics, University Hospital Regensburg- St. Hedwig Clinic, Germany
• Udo Markert, Placenta-Labor, Universitätsklinikum Jena, Jena, Germany
• Volker Daniel, Transplantation Immunology, Institute of Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany
• Dr. Dr. Ruben Kuon, Department of Gynecological Endocrinology and Fertility Disorders, Heidelberg University Hospital, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
• Rienk Nieuwland, UMC Research Institutes, Amsterdam, Netherlands
• -Prof.ⁱⁿ Dr.ⁱⁿ Magdalena Flatscher- Thoeni, UMIT – University for Health Sciences, Medical Informatics and Technology, Hall in Tyrol, Austria