The role of inactive follicle stimulating hormone in ovarian dysfunction in galactosemia.

Classical galactosemia is an inborn error of galactose metabolism due to a
deficiency of the enzyme galactose-1-fosfate uridyltransferase. Dairy products
are rich in galactose. Treatment consists of a lifelong galactose restricted
diet (soja diet).
Most females with galactosemia have ovarian dysfunction varying from primary to
secondary amenorrhoea due to premature ovarian failure and was first described
by Kaufman et al. in 1981. In 75-90% primary amenorrhoea is present and women
are infertile.
Until present the mechanism underlying ovarian dysfunction is not clear.
Recent insights point to a possible inactive (follicle stimulating hormone) FSH
in these patients.

FSH is such as other hormones a glycoprotein (protein with sugar trees). In
classical galactosemia there is a secondary disturbance in glycosylation of
proteins (abnormal sugar trees are made). Protein glycan structures (sugar
trees) are essential for protein function. In female galactosemia patients,
there is preliminary evidence that abnormally glycosylated FSH is present. This
abnormal glycosylated FSH can bind to the receptor but it is unable to generate
cyclic AMP, acting as an antagonist. The final result is that no estradiol
(female hormone) can be produced.
Our hypothesis is that ovarian dysfunction in galactosemia females is due (at
least in part) to inactive, abnormally glycosylated FSH.

Clinical relevance: Most women with classical galactosemia are infertile. If
ovarian dysfunction is due to inactive FSH, treatment with exogenous FSH and LH
could be a possibility in childbearing women. Moreover this finding would be
very relevant for the understanding of this disease complication and for
possible elucidation of other complications (abnormal glycosylation of other
proteins).

1) To assess whether galactosemia women with ovarian failure are able to
produce estradiol after exogenous (normally bioactive) FSH and LH gift
2) To characterize FSH glycan structures

Intervention study with before and after measurements and no parallel group

Study persons are treated with one subcutaneous gift Menopur, 150 resp 225
IU/day during maximum 20 days. This is registered medication regularly used for
ovulation induction in infertility treatment.
Just before the first gift and on day 8, 10, 18 and 20, a blood sample is drawn
(vena punction, 10 ml each time).

Most women with galactosemia have ovarian dysfunction and are infertile. The
mechanism is not yet clear. Female patients often experience this complication
as the most distressing problem of their disease.
If we obtain a positive estradiol response in this study after FSH and LH
stimulation, we will be a huge step forward in understanding the mechanism
underlying this complication and treatment of infertility in this women.
The study lasts a maximum of 20 days and the expected risks of this treatment
are, with this relatively low dose, extremely small. The injections and blood
withdrawals are done by the at the patient's home address. In case of
complaints, the patient can contact the physician researcher 24 hours/day.
Adverse effects of Menopur are described in paragraph 7.2 of the protocol.
The participants will be notified of the results of the study.