Does a Positive Oestrogen Feedback on the Hypothalamic-Pituitary Axis Exist Concurrently with a Defective Testosterone Feedback in Klinefelter’s Syndrome?

Abstract

The oestrogen provocation and GnRH challenge tests were carried out in 5 subjects with Klinefelter’s syndrome who had no history of previous hormonal therapy. The oestrogen provocation test consisted of an intramuscular injection of 10 mg of oestradiol valerate and blood samples were collected daily from day 0 to day 5. In 2 subjects, three GnRH challenge tests were carried out before (day 0) and on days 2 and 4 after the intramuscular injection of oestradiol valerate. During each GnRH challenge test, 7 blood samples were collected at 30-min intervals, 30 min and immediately before and for 150 min after the bolus dose of GnRH. Plasma concentrations of FSH, LH, testosterone and oestradiol were measured by established radioimmunoassays. Plasma levels of oestradiol rose significantly a day following the intramuscular injection of 10 mg of oestradiol valerate, reaching a peak on day 2 and then falling significantly to lower levels by days 4 and 5, although these levels were still significantly higher than the corresponding baseline levels. In the presence of high levels of oestradiol, the high basal levels of FSH were significantly suppressed, and remained suppressed throughout the 5 days of the study. LH, on the other hand, had a biphasic response; an initial significant suppression by day 1 persisting to day 3, but by days 4 and 5 a rebound in basal LH levels was noted. However, the levels on day 5 were not significantly higher than baseline levels. The pituitary responsiveness as far as the LH and FSH secretions were concerned reflected the baseline levels. The results of the present study refuted the claim that a positive oestrogen feedback exists in men including Klinefelter’s syndrome as a result of the removal of or reduced testosterone. In addition, the attenuated testosterone feedback in Klinefelter’s syndrome is responsible for the greatly amplified pituitary responsiveness to the trophic action of GnRH and this, in part, may be responsible for the elevated levels of FSH and LH seen in such patients.

Further Evidence of the Clinical, Hormonal, and Genetic Heterogeneity of Klinefelter Syndrome: A Study of 216 Infertile Egyptian Patients

“…On the other hand, normal serum gonadotropin levels in association with KS have been reported in the literature (Carter et al, 1977; Advani et al, 1991). This discrepancy could be explained by exhaustion of gonadotropin levels as a result of previous prolonged hypersecretion (Goh and Lee, 1998), or the finding may be a simple association. Alternatively, the response to LH‐releasing hormone might be normal in these patients (Carter et al, 1977).…”

“…One of these substances could be E2, as evidenced by the inverse correlation between E2 levels and LH. However, the hypothesis that positive estrogen feedback occurs in KS as a result of removal of, or reductions in, testosterone has been refuted (Goh and Lee, 1998). On the other hand, normal serum gonadotropin levels in association with KS have been reported in the literature (Carter et al, 1977; Advani et al, 1991).…”

Relative hyperestrogenism in Klinefelter Syndrome: results from a meta-analysis

“…A total of 65 articles were considered (see Supplemental Table 1, Supplemental Table 2, Supplemental Table 3, and Supplemental Table 4 for further details) [38]. Of these, 23 case-control studies [6, 16, 17, 19, 22-29, 40, 50-58], 14 case series [14,34,[59][60][61][62][63][64][65][66][67][68][69][70], and 19 case reports (all listed in Supplemental Data) [38] reported data on serum estradiol and were included in the analyses (Fig. 1).…”