Aspects on puberty and fertility among females with cystic fibrosis a multidisciplinary study on humans and rats

Due to intensified symptomatic treatment, a majority of patients with cystic fibrosis (CF) now go through puberty and reach adulthood. This provides new challenges for the CF health care providers. Delayed puberty and decreased fertility seen in CF females have been suggested to be caused by malnutrition and impermeable cervical mucus resulting from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein.

The main purpose of this thesis was to highlight factors contributing to developmental and reproductive status by retrospectively studying pubertal development and prospectively studying pathophysiology behind reduced fertility in CF women. We also wanted to study psychosocial issues concerning puberty and motherhood among CF women, how they had obtained and conceived information in these matters and how they would like information to be given. CFTR and multidrug resistance (MDRlb) proteins are members of the "ATP-binding cassette" superfamily of transporters. They are associated with chloride channel activities and ATP secretion and have complementary patterns of expression in several organs. We wanted to study CFTR mRNA expression in hypothalamic areas important for sexual maturation and reproduction in female rats and whether CFTR resp. MDRlb mRNA expression in rat lung change during pregnancy.

Pubertal delay still existed among CF women despite good clinical status. The more delayed puberty in patients homozygous for the most common mutation (delta F508) and those with pathological glucose tolerance test may be due to increased resting energy expenditure and defective insulin secretion. However, the low levels of essential fatty acids (EFA) is probably also a factor behind the delayed puberty. The cause of reduced fertility among these CF women appears more complex than previously thought. The data indicate that a primary ovarian disorder is involved. The unexpected high rate of anovulation in CF women with good clinical status may be explained by more profound EFA deficiency, signs of hyperinsulin secretion and higher androgen levels compared to the CF women who ovulate. However, all but one CF patient responded with ovulation to the clomiphene citrate stimulation treatment indicating a normal ovarian response. The high androgen levels and signs of hyperinsulinemia resemble that of women with polycystic ovarian syndrome. It is still possible that defective neuroendocrine regulation in CF may be one causative factor to disturbed hormonal balance in these women.

CFTR mRNA was expressed in the medial preoptic area in hypothalamus in female rats addressing the possibility of CFTR regulation of sexual maturation and reproductive behaviour. CFTR mRNA was also found in cortical deep pyramidal layer V implying possible involvement of CFTR in "motor" function and output control over bodily movements and secretion. CFTR might act via acidification of synaptic vesicles and thereby regulate neurotransmission and secretion of neuropeptides. Disturbances in CFTR production in the brain regions observed could thus lead to impaired cerebral control over motor/visceral and endocrine systems and thereby accentuate pathology seen in CF patients. No variations in CFTR or MDRlb mRNA levels in the lungs during pregnancy were detected. However, there was an unusual degree of variation in MDRlb mRNA expression in lung parenchyma between animals in both the control and pregnant group. This may relate to humans, where increased expression in MDRI in the airways correlated with reduced lung symptomatology in a CF patient undergoing chemotherapy. A defective CFTR channel protein might be partly compensated by a functioning MDRI protein.

Our study showed that CF females need special education and counseling concerning their health, pubertal development and fertility especially during the years of adolescence. Information about puberty and fertility should be given individually and in small discussion groups with teenage girls combined with thorough medical and psychological guidance concerning motherhood for the adult CF females.