In the ReproHealth team, clinical research is combined with in vitro tissue modeling and modeling with human pluripotent stem cells.
Stem cell models

Most or our knowledge on gonadal development stems from studies in animal models. However, there are crucial developmental differences between species, and the development of human gonads is surprisingly poorly known. We utilize human embryonic (ESC) and induced (iPSC) pluripotent stem cells to model the development of the somatic cells of the gonads, i.e. the Sertoli cells of the testes and the granulosa cells of the ovaries.

Our aims are:

  1. to increase our understanding of the embryonic gonadal development in human
  2. to generate models for studying the molecular mechanisms of disorders of sexual development (DSD) by studying specific genes, and
  3. to establish in vitro models for testing the effect of potential drugs and suspected endocrine disrupters on stem cell-derived Sertoli and granulosa cells and hence on fertility.
Clinical research projects

Long-term health consequences of polycystic ovary syndrome (PCOS)

A common female endocrinopathy, PCOS affects 10% to 15% of women. Characterized by anovulation, hyperandrogenism, chronic inflammation, and unbeneficial lipid profile, it often manifests as irregular menstruation and infertility in fertile age women, but later in life women with PCOS present increased risks for type 2 diabetes and cardiovascular diseases.

The projects concerning PCOS deal with long-term risks and health consequences. Special emphasis in these studies includes lipid metabolism, type 2 diabetes and cardiovascular morbidity and preventive treatments.

Metabolic effects of combined hormonal contraceptives

Combined hormonal contraception (CHC) has been widely used since the 1960s. There are currently an estimated 100 million fertile-age users of combined contraception in the world. In Finland, CHC is used by about 200,000 women. CHCs have been linked to worsened glucose tolerance. Reduced glucose tolerance has been associated particularly with preparations containing high-dose ethinyl estradiol and androgenic progestins. Recently, the use of CHC in late fertile age has been associated with an increased risk for type 2 diabetes.

The projects are aimed to study and compare the metabolic effects of CHCs containing different estrogen and progestin components. Special interest is in studies comparing traditional ethinyl estradiol and newer natural estradiol containing preparations.

Parity and gynecological cancer

Pregnancy is associated with significant changes in the metabolic and hormonal state. Circulating levels of sex steroids during pregnancy are 10–100 times higher than in nonpregnant women, which influences many functions of reproductive and other organs. There is strong evidence that parity and especially multiparity decreases the risk of breast and gynecological cancers.

In this project we focus on the risks of different epithelial ovarian cancer types and endometrial cancer, and granulosa cell tumors in nulliparous and parous women using the data from the Finnish Cancer Register and the Finnish Population Register.

Embryo research

Human preimplantation development from fertilized oocyte to implanting blastocyst lasts 5-6 days during which the number of cells multiply from one to roughly one hundred and also the first developmental lineages are established. Our project heads to reval how the development is regulated at genetic and epigenetic level and also, how in vitro conditions may affect the control of gene expression.

Ovary research

According to current understanding, all oocytes present in ovaries are formed during the fetal period. Each oocyte is enclosed by a single layer of granulosa cells forming a structure known as primordial follicle. Primordial follicles may remain at resting stage for years and they provide the unrenewable stock of female germ cells. Once the follicles start to grow, granulosa cells surrounding the oocyte start to proliferate and the oocyte begins to enlarge. In human, the maturation from the primordial to ovulating follicle containing developmentally competent mature oocyte takes approximately three months. Ovarian stroma surrounding follicles consists of various cell types including poorly characterized fibroblasts and stem cells forming e.g. theca cells. The function of the stroma is not only to provide mechanical support for follicles, but it actively contributes to regulation of folliculogenesis and the reproductive cycle.

Today the survival rate for childhood cancers is over 80% and most children diagnosed with cancer can expect to live for decades, making quality of life issues, such as fertility, highly important. As cancer treatments may be deleterious for the ovaries, ovarian tissue cryopreservation can be offered to preserve fertility in young girls. Frozen-thawed ovarian tissue from adults has been successfully transplanted back to the patients, but only a couple of pregnancies have been reported after transplantation of ovaries stored before puberty and none when tissue preservation has been done for girls younger than 9 years old. Indeed, the structure and function of child ovaries in humans is poorly characterized and we do not know the effects of freezing and thawing at cellular level. In the mouse there are different categories of small follicles with distinct age-dependent functions and not all follicles in prepubertal mice are involved in reproduction. Whether similar functionally different follicles exist in humans is not known. Also, fertility preservation is typically offered for children only if first-line cancer treatment does not work or the disease relapses. The gonadotoxic insult caused by chemotherapy has not been analyzed in detail but leads to deterioration of tissue quality. Evaluating the survival of child tissue in cancer treatment and tissue cryopreservation challenges requires comprehensive understanding of the structure and function of the tissue at molecular level and this is currently missing.

In our study, we will characterize follicular and stromal cellular composition in child and adult ovaries to reveal age and maturity dependent differences in transcriptional activity by combining several sequencing and imaging methods. We analyze how freezing and thawing as such affects child and adult ovarian tissue by profiling gene expression patterns in follicles and stromal cells before and after freezing. Importantly, we will also evaluate the effect of commonly used chemotherapeutic drugs on the health of child ovarian tissue and follicles to reveal the impact of the treatment on the developmental competence of follicles in prepubertal ovaries.