Dehydroepiandrosterone sulfate levels reflect endogenous luteinizing hormone production and response to human chorionic gonadotropin challenge in older female macaque (Macaca fascicularis)

Abstract

Objective: We propose that the adrenal gland of an older higher primate female animal model will respond to human chorionic gonadotropin (hCG) hormone challenge by secreting additional dehydroepiandrosterone sulfate (DHEAS). Such a response in surgically and chemically castrated animals will provide proof of concept and a validated animal model for future studies to explore the rise in DHEAS during the menopausal transition of women.

Methods: Twenty-four 18- to 26-year-old female cynomolgus monkeys were screened for ovarian function and then either ovariectomized (n = 4) or treated with a gonadotropin-releasing hormone agonist (GnRHa; n = 20) to block ovarian steroid production. After a recovery period from surgical procedure or down-regulation, a single-dose challenge (1,000 IU/animal, IM) of hCG was then administered to determine if luteinizing hormone (LH)/chorionic gonadotropin could accelerate circulating DHEAS production. Serum DHEAS, bioactive LH, and urinary metabolites of ovarian sex steroids were monitored before, during, and after these treatments.

Results: Circulating LH bioactivity and immunoreactive DHEAS concentrations were suppressed in all animals 14 days postadministration of GnRHa. Urinary metabolites of estradiol and progesterone remained low after the surgical procedure or a flare reaction to GnRHa. Circulating DHEAS levels were increased after hCG administration, and the increase in individual animals was proportional to the pretreatment DHEAS at baseline. Circulating DHEAS concentrations were positively correlated to endogenous LH bioactive concentrations prior to hCG challenge and were subsequently further elevated by the hCG challenge while no concomitant change in ovarian steroid hormone excretion was observed.

Conclusions: These data demonstrate a positive adrenal androgen response to LH/chorionic gonadotropin in older female higher primates and suggest a mechanism for the rise in adrenal androgen production during the menopausal transition in women. These results also illustrate that the nonhuman primate animal model can be effectively used to investigate this phenomenon.

FIG. 1

Mean serum DHEAS concentration relative to GnRHa treatment in aging female macaques. A single dose (0.25 mg/kg of body weight) of GnRHa (leuprolide acetate) was administered intramuscularly. DHEAS was measured in serum obtained before (baseline), 2 days after, and 14 days after the GnRHa injection. Friedman repeated-measures analysis of variance on ranks was conducted for comparison. Levels not linked by the same letter indicate a statistically significant difference (P<0.05). DHEAS, dehydroepiandrosterone sulfate; GnRHa, gonadotropin-releasing hormone agonist.

FIG. 2

Mean urinary estrogen metabolite (estrone conjugate [E₁C]) concentration indexed by CR concentration before and after GnRHa treatment in aging female macaques. A single dose (0.25 mg/kg of body weight) of GnRHa (leuprolide acetate) was administered intramuscularly. Friedman repeated-measures analysis of variance on ranks was conducted for comparison. Levels not linked by the same letter indicate a statistically significant difference (P<0.05). CR, creatinine; GnRHa, gonadotropin-releasing hormone agonist.

FIG. 3

Mean urinary progesterone metabolite (pregnanediol glucuronide [PdG]) concentration before and after GnRHa treatment in aging female macaques. A single dose (0.25 mg/kg of body weight) of GnRHa (leuprolide acetate) was administered intramuscularly. Friedman repeated-measures analysis of variance on ranks was conducted for comparison. Levels not linked by the same letter indicate a statistically significant difference (P<0.05). CR, creatinine; GnRHa, gonadotropin-releasing hormone agonist.

FIG. 4

Mean urinary estrogen metabolite (estrone conjugate [E₁C]) concentration indexed by CR concentration before, 1 day after, and 2 days after hCG treatment in aging female macaques. A single dose (1,000 IU/animal) of hCG (NOVAREL) was administered intramuscularly 14 days after GnRHa treatment. CR, creatinine; GnRHa, gonadotropin-releasing hormone agonist; hCG, human chorionic gonadotropin.

FIG. 5

Mean urinary progesterone metabolite (pregnanediol glucuronide [PdG]) concentration before, 1 day after, and 2 days after hCG treatment in aging female macaques. A single dose (1,000 IU/animal) of hCG (NOVAREL) was administered intramuscularly 14 days after GnRHa treatment. CR, creatinine; GnRHa, gonadotropin-releasing hormone agonist; hCG, human chorionic gonadotropin.

FIG. 6

Mean serum DHEAS concentration relative to hCG treatment in aging female macaques. A single dose (1,000 IU/animal) of hCG (NOVAREL) was administered intramuscularly 14 days after GnRHa treatment. DHEAS was measured in serum samples before and at several time points after hCG treatment. Friedman repeated-measures analysis of variance on ranks was conducted for comparison. Levels not linked by the same letter indicate a statistically significant difference (P<0.05). DHEAS, dehydroepiandrosterone sulfate; GnRHa, gonadotropin-releasing hormone agonist; hCG, human chorionic gonadotropin.

FIG. 7

Mean bioactive LH concentration relative to GnRHa treatment in aging female macaques. A single dose (0.25 mg/kg of body weight) of GnRHa (leuprolide acetate) was administered intramuscularly. Bioactive LH in the three serum samples before the hCG challenge was measured for LH. Friedman repeated-measures analysis of variance on ranks was conducted for comparison. Levels not linked by the same letter indicate a statistically significant difference (P<0.05). GnRHa, gonadotropin-releasing hormone agonist; LH, luteinizing hormone.