A Sex Divergence in Pulsatile GH Secretion, Ghrelin/GHRH-Stimulated GH Secretion, and SHBG Concentration Responses to the SERM, Toremifene, in Older Adults

Presentation Number: SUN 426
Date of Presentation: April 2nd, 2017

Johannes D. Veldhuis1, Rebecca Y. Yang2, Paul Y. Takahashi3, Dana Erickson*3 and Cyril Y Bowers4
1Mayo Clinic School of Medicine, Rochester, MN, 2Mayo Cinic, Rochester, MN, 3Mayo Clinic, Rochester, MN, 4Tulane University Health Sciences Center, New Orleans, LA


Antiestrogens and estrogen-receptor modulators exert general metabolic actions in part via effects on liver, fat, bone and the pituitary gland itself. Whether sex differences exist in such effects is not known. We hypothesized that the antiestrogen, toremifene, used in treatment of breast and prostate cancer, disrupts GH outflow and IGF-I availability differentially in men and women. Nineteen healthy women (ages 64 ± 1.2 yr) and 20 men (ages 66 ± 1.0) were recruited from the Olmsted community, having comparable BMI, fasting plasma glucose, albumin and total abdominal fat by CT scan at the Mayo Clinical Translational Research Center. The intervention was a double-blind, prospective, randomized treatment with placebo or toremifene (60 mg/ daily) for 10 day in a crossover design, allowing >3 wk intervening. Deconvolution analysis was performed of 10-min GH time series collected for 12 h overnight (2200-1000 h). A 0.3 µg/kg iv bolus of ghrelin and GHRH was given at 0800 h to test pituitary responsiveness. Mass spectrometry was used for quantification of sex steroids. None of T, E2 or E1 changed within gender on toremifene vs placebo. IGF-I (µg/L) fell from 108 ± 6.6 to 85 ± 5.1 in men (P=0.005) and from 104 ± 7.0 to 84 ± 7.4 in women (P=0.030), but IGFBP-3 did not change in either sex. SHBG rose in men only (P=0.032). Pulsatile GH secretion (µg/L over 10-h before ghrelin/GHRH injection) declined from 19 ± 3.1 (placebo) to 13 ± 2.2 (toremifene) in men (P=0.030), with no change in women. The men’s overnight GH response was attributed to a decrease in GH secretory-burst frequency, viz., 6.2 ± 0.48 (placebo) and 4.5 ± 0.37 (toremifene) (P=0.024 contrast). In women, toremifene augmented basal (nonpulsatile) GH secretion by 30% (P=0.021). The antiestrogen potentiated combined ghrelin/GHRH-stimulated mean and peak GH concentrations, and the mass of GH secreted per 3 h, in men (P=0.031) but not in women. Conclusion: Whereas the antiestrogen, toremifene, stimulates SHBG, inhibits pulsatile overnight GH secretion due to pulse-frequency deceleration, and heightens ghrelin/GHRH-stimulated GH secretion in men, none of these effects occurs in women. We hypothesize that in men this antiestrogen exerts estrogen-like effects on liver (increased SHBG, blocked GH action on IGF-I) and pituitary (increased ghrelin/GHRH action) and inhibitory (antiestrogenic) effects on hypothalamus (reduced GH pulse frequency overnight). The exact basis for this strong sex difference is not yet known.


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