α-Estrogen and Progesterone Receptors Modulate Kisspeptin Effects on Prolactin: Role in Estradiol-Induced Prolactin Surge in Female Rats

Abstract

Kisspeptin (Kp) regulates prolactin (PRL) in an estradiol-dependent manner. We investigated the interaction between ovarian steroid receptors and Kp in the control of PRL secretion. Intracerebroventricular injections of Kp-10 or Kp-234 were performed in ovariectomized (OVX) rats under different hormonal treatments. Kp-10 increased PRL release and decreased 3,4-dihydroxyphenylacetic acid levels in the median eminence (ME) of OVX rats treated with estradiol (OVX+E), which was prevented by tamoxifen. Whereas these effects of Kp-10 were absent in OVX rats, they were replicated in OVX rats treated with selective agonist of estrogen receptor (ER)α, propylpyrazole triol, but not of ERβ, diarylpropionitrile. Furthermore, the Kp-10-induced increase in PRL was two times higher in OVX+E rats also treated with progesterone (OVX+EP), which was associated with a reduced expression of both tyrosine hydroxylase (TH) and Ser40-phosphorylated TH in the ME. Kp-10 also reduced dopamine levels in the ME of OVX+EP rats, an effect blocked by the progesterone receptor (PR) antagonist RU486. We also determined the effect of Kp antagonism with Kp-234 on the estradiol-induced surges of PRL and luteinizing hormone (LH), using tail-tip blood sampling combined with ultrasensitive enzyme-linked immunosorbent assay. Kp-234 impaired the early phase of the PRL surge and prevented the LH surge in OVX+E rats. Thus, we provide evidence that Kp stimulation of PRL release requires ERα and is potentiated by progesterone via PR activation. Moreover, alongside its essential role in the LH surge, Kp seems to play a role in the peak phase of the estradiol-induced PRL surge.

Reduced dopaminergic tone during lactation is permissive to the hypothalamic stimulus for suckling‐induced prolactin release

“…45 In the supernatant, dopamine and DOPAC concentrations were determined as described previously. 16,46 Briefly, chromatography separations were performed using a C-18 column (250 × 4 mm, 5 µm; Merck, Darmstadt, Germany) preceded by C18 pre-column (5 μm, 4 × 4 mm; Merck) and kept at 40°C. The mobile phase consisted of 100 mmol L -1 Twenty microliters of each sample were injected into the HPLC system, and chromatographic data were plotted using Class-VP software (Shimadzu Corp., Kyoto, Japan).…”

“…Plasma PRL levels were assayed using rat PRL ELISA, as described previously. 46 Briefly, the reference preparation used was rat PRL…”

“…TH is the rate-limiting step in dopamine biosynthesis 1 of dopaminergic neurones. 10,26,46 To determine whether suckling could acutely suppress the activity of TH, we performed immunofluorescence double labelling for TH and S 40 pTH in the ME. Figure 4 shows representative photomicrographs of TH and S 40 pTH labelling in the ME.…”

Kisspeptin and Prolactin

“…116 We have also reported that TIDA neurons in both males and females express ERα, whose selective activation is necessary and sufficient to make prolactin responsive to kisspeptin. 116,117 In agreement with the kisspeptin effects on TIDA neurons, kisspeptin-10 has been recently shown to reduce dopamine release from the rat hypothalamic cell line Hypo-E22. 118 Nevertheless, these findings are in contrast to those of Navarro et al, 119 who also investigated the effect of ICV kisspeptin-10 on prolactin secretion in rats.…”

“…We have shown that ICV injection of kisspeptin-234, a selective antagonist of Kiss1r, impaired the peak phase of the estradiol-induced prolactin surge alongside the blockade of the preovulatory-like LH surge in OVX þ E2 rats. 117 This is of particular interest as it suggests that there may also be a link from the RP3V kisspeptin population to the stimulation of prolactin secretion, either through inhibition of TIDA neurons or through activation of a PRF. Such a mechanism awaits further elucidation.…”