DISCOVERING NEW INSIGHTS

FREIA will gain new understandings and insights into adverse effects of endocrine disruption on women’s health.


Many concerns about potential effects of EDCs on human and wildlife reproductive health originate from findings linking exposure to environmental estrogens and antiandrogens in the womb to declining sperm counts and increasing prevalence of undescended testes, testicular cancer and urinary duct malformation in male offspring. It was long assumed that males were more sensitive to adverse effects of EDCs than females. As a result, there is a clear under-representation of research into the potential effects of EDCs on female reproduction, which is thought-provoking considering that the finite reserve of ovarian follicles is clearly a significantly more limiting factor in human reproduction than the production of sperm.

The number of women with fertility problems is increasing globally. Clinical studies show that up to 20% of women in reproductive age are affected by ovarian disorders such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and irregular menstrual cycles. Up to 15% of couples worldwide face infertility and increasingly artificial techniques are needed to establish pregnancy. Clearly, female reproduction is not insensitive to endocrine disruption, as overt reproductive effects have been described in humans, for example for the synthetic estrogen diethylstilbestrol (DES).

DIFFERENT LIFE STAGES, DIFFERENT EFFECTS

At birth, a baby girl has approximately three hundred thousand primordial follicles constituting the ovarian reserve. It would be logical, therefore, to assume that after follicle formation is completed early in the last trimester of pregnancy, the impact of chemicals on ovarian reserve would then be the same in children, adolescents and adults. However, there are reports suggesting differences in basic follicle biology in young girls and adult women that may lead to different effects of EDCs. Moreover, many hormonal processes are activated or reactivated in the transition from child to adulthood, thereby posing a potentially sensitive phase in life for EDC exposure.

IN THE WOMB

After decades of clinical use, it was found that DES causes cancer of the female reproductive tract, impaired fertility, endometriosis and earlier menopause in the daughters born from women taking these drugs during pregnancy. This strengthens the notion that there is a common, developmental origin leading to altered ovarian structure or function and female reproductive disorders in adulthood. The mechanistic aspects on ovarian development in the human fetus by EDCs are presently unknown.

PUBERTY

The onset of female puberty relies on appropriate activation of hormonal signalling. With the onset of puberty, ovarian follicles are periodically recruited to restart growth and become increasingly responsive to hormonal stimulation. This hormonal signalling and the onset of puberty are both susceptible to disturbances following exposure to EDCs. Changes in female puberty timing are seen for phthalates and bisphenol A, and have been associated with delayed or precocious onset of puberty. In humans, this is known more specifically for early breast development in girls in which the role of EDCs has been discussed over the last decades. Clearly, EDCs can affect processes underlying the onset of puberty, yet it needs to be established which processes during which times in life are crucial and how this may affect fertility later in life.

ADULTHOOD

During a woman’s reproductive life (outside of pregnancy and lactation), normally only a single oocyte completes the maturation process every month until menopause marks the end of the ability to conceive a child. Approximately 400 follicles will eventually mature to the ovulatory stage. For this, the right amount of hormones need to be produced by the ovaries at the right time in the menstrual cycle. EDCs are known to affect the production of hormones, but it is yet to be determined how the ovarian production of hormones is affected. EDC exposure during adulthood can cause a range of effects such as menstrual cycle abnormalities, decreased pregnancy rates, and increased onset of reproductive senescence. Whether EDCs can affect follicle growth, maturation and death in women has not yet been thoroughly addressed.