We evaluated gonadal function in 18 female and eight male patients with galactosemia due to transferase deficiency; it was normal in the males, but 12 females had signs of hypergonadotropic hypogonadism. All female patients had a 46,XX karyotype, normal levels of thyroid hormone and prolactin, and no anti-ovarian antibodies. The biologic activity of urinary gonadotropins was normal. Ultrasonography of the pelvis revealed that ovarian tissue was diminished or absent. Total estrogens increased in one of two patients after administration of human menopausal gonadotropin. The frequency of hypergonadotropic hypogonadism was higher in females in whom dietary treatment for galactosemia was delayed. Clinical course and mean erythrocyte galactose-1-phosphate and urinary galactitol levels did not correlate with ovarian function. We conclude that female patients with galactosemia have a high incidence of ovarian failure due to acquired ovarian atrophy. Galactose or its metabolites may be toxic to the ovarian parenchyma, particularly during the immediate neonatal period.

No abstract

Two siblings with 46,XY male pseudohermapthroditism were demonstrated to have the phenotype characteristic of 5 alpha-reductase deficiency, namely normal testes and male Wolffian duct derivatives (epididymis, vas deferens, and seminal vesicle) terminating in a blind-ending vagina. Clitoromegaly was present at birth and increased further at the time of expected puberty. The diagnosis of 5 alpha-reductase deficiency was confirmed by demonstration of male levels of testosterone and testosterone precursors before and after hCG administration, elevated plasma testosterone to dihydrotestosterone and urinary etiocholanolone to androsterone ratios, and by in vitro studies indicating 5 alpha-reductase enzyme deficiency in the epididymis of one patient. Studies of control and mutant epididymal microsomes indicated that a single enzyme is responsible in the normal person for the 5 alpha-reduction of testosterone and cortisol (and probably other delta 4-3-ketosteroids as well) and that 5 alpha-reductase activity is undetectable for all substrates examined in the mutant. This finding explains why the formation of 5 alpha-reduced glucocorticoids is also defective in the disorder.

Gonadal function was followed in 26 females and 12 males with galactosaemia due to deficiency of the enzyme galactose-1-phosphate (Gal-1-P) uridyl transferase over a 4 year period. Gonadal function was normal in males, but all females except two had evidence of acquired ovarian failure. Twelve females with ovarian failure documented at the beginning of this study continued to have either primary or secondary amenorrhoea on follow-up. Five of six patients, who previously had normal gonadal function developed either hypergonadotrophic hypogonadism or an abnormal response to gonadotrophin-releasing hormone (LRH) indicative of acquired ovarian damage. Seven of eight female patients, 1-12 years of age, who were evaluated for the first time had an exaggerated release of gonadotrophins during LRH stimulation tests diagnostic of gonadal insufficiency. The pathogenesis of ovarian failure remains unknown, but it appears likely that galactose or Gal-1-P is toxic to the ovary. The source of galactose metabolites, which may begin to accumulate prenatally and continue to damage the gonad in the postnatal period, is likely to be derived from the diet and from the endogenous synthesis of Gal-1-P from glucose via a variety of metabolic pathways. The testis appears to be relatively resistant to the effects of abnormal galactose metabolism.