In this review, Dr. Iremonger summarizes recent studies demonstrating the plasticity and local regulation by neurotransmitters and hormones of the neuroendocrine terminal at the median eminence. A conceptual view of an independent regulation of neuroendocrine nerve terminals to integrate signals and control the endocrine axes is proposed. Specifically, examples regarding the gonadal, prolactin, thyroid, and adrenal axes are presented. The review is up to date and interesting to the neuroendocrinology audience. As a main concern, sometimes the text seems superficial in key concepts and critical points of view regarding methodology and mechanism. As the text is considerably short, the review would benefit from a deeper exploration of the subject. Some specific comments are provided below.
1. The lines and pages are not marked in the text, which would facilitate the revision process.
2. Abstract. This section seems too succinct and does not fully cover what is going to be addressed in the review, which would be required to attract the reader’s attention.
3. Introduction. The statement “The median eminence lacks a blood-brain barrier and is therefore classed as a circumventricular organ” requires referencing and would need deeper description and explanation.
4. The statement “Tanycytes play an essential role in regulating nerve terminal function as well as controlling as well as controlling the diffusion of molecules into and out of the median eminence4,5” would need further explanation. How does this mechanism happen?
5. Between the Introduction and the GnRH nerve terminal section, the text misses a paragraph describing why and how the subject addressed is relevant.
6. About the statement “These changes allow for more GnRH terminals to be directly in contact with portal vessels and which should facilitate the diffusion of GnRH into the portal vasculature”, what is the evidence that GnRH diffusion to the portal blood is altered?
7. Please, define all abbreviations in the first use, e.g., PGE2, TGF-B1, Sema7A, VGlut2, etc.
8. About the discussion of references 16 to 20, it is not clear in the text how the actions of kisspeptin and other neurotransmitters on the GnRH cell body are excluded in the experimental protocols to claim only local action at the median eminence.
9. In the statement “Within the median eminence, there is co-expression of the dopamine transporter (DAT) and TH27-29. This opens up the possibility that the degree of dopamine autoregulation at TIDA nerve terminals could be modulated by dopamine reuptake”. Check citation of reference 27 for accuracy. Moreover, it is unclear why dopamine autoregulation would be modulated by its reuptake. This requires further explanation of such a mechanism.
10. In the statement “This has led to the idea that TIDA neurons may undergo a process known as neurotransmitter switching33”. The process of neurotransmitter switching is mentioned but not explained. Thus, the text would benefit from a more detailed explanation of its nature and regulation.
11. In the statement “This also appears to be the case in CRH nerve terminals in the median eminence, which express both GABAA receptors as well as NKCC1, the Na+-K+-2Cl- cotransporter54. This co-transporter maintains a high intracellular Cl-”. The cell membrane mechanism is not clear and could be further explained.
12. Figure 1 is too simplified and, therefore, provides only a limited understanding of the mechanisms being exemplified. As examples, in A, the effects of estradiol and progesterone are not clear. In B, what is the role attributed to dopamine and the dopamine receptor in this mechanism? Also, part of the figure legend is missing in the text.

The author has properly answered the comments made and improved the manuscript. I have only one additional comment related to my original comment #9, as described below.

1. In the statement “Within the median eminence, there is co-expression of the dopamine transporter (DAT) and TH27-29. This opens up the possibility that the degree of dopamine autoregulation at TIDA nerve terminals could be modulated by dopamine reuptake”. Check citation of reference 27 for accuracy. Moreover, it is unclear why dopamine autoregulation would be modulated by its reuptake. This requires further explanation of such a mechanism.

Author’s response: Reference 27 in the original manuscript is correct- this reference shows that TIDA nerve terminals have functional DAT. The level of DAT will directly determine the local concentration of dopamine and hence the extent of activation of dopamine autoreceptors. This has been more explicitly stated.

Related to the reference citation, the statement in the text is “Within the median eminence, there is co-expression of the dopamine transporter (DAT) and TH31-33”. I note that this is not shown in the study by Stagkourakis et al 2019 (reference 27, 31 in R1). Therefore, for consistency, either the sentence should be rephrased or the reference removed. Moreover, to my knowledge, there is no evidence to support the assumption that “The level of DAT will directly determine the local concentration of dopamine and hence the extent of activation of dopamine autoreceptors”. Especially considering the dynamics of neuroendocrine dopaminergic terminals in the median eminence. Thus, this statement requires a reference citation or an explanation that it is the author’s hypothesis.