Ablation of KNDy neurons results in hypogonadotropic hypogonadism and amplifies the steroid-induced lh surge in female rats

Melinda A. Mittelman-Smith, Sally J. Krajewski-Hall, Nathaniel T. McMullen, Naomi E Rance

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

In the human infundibular (arcuate) nucleus, a subpopulation of neurons coexpress kisspeptin and neurokinin B (NKB), 2 peptides required for normal reproductive function. A homologous group of neurons exists in the arcuate nucleus of rodents, termed KNDy neurons based on the coexpression of kisspeptin, NKB, and dynorphin. To study their function,werecently developed a method to selectively ablate KNDy neurons using NK3-SAP, a neurokinin 3 receptor agonist conjugated to saporin (SAP). Here, we ablated KNDy neurons in female rats to determine whether these neurons are required for estrous cyclicity and the steroid induced LH surge. NK3-SAP or Blank-SAP (control) was microinjected into the arcuate nucleus using stereotaxic surgery. After monitoring vaginal smears for 3-4 weeks, rats were ovariectomized and given 17-estradiol and progesterone in a regimen that induced an afternoon LH surge. Rats were killed at the time of peak LH levels, and brains were harvested for NKB and dual labeled GnRH/Fos immunohistochemistry. In ovary-intact rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, characterized by low levels of serum LH, constant diestrus, ovarian atrophy with increased follicular atresia, and uterine atrophy. Surprisingly, the 17-estradiol and progesterone-induced LH surge was 3 times higher in KNDy-ablated rats. Despite the marked increase in the magnitude of the LH surge, the number of GnRH or anterior ventral periventricular nucleus neurons expressing Fos was not significantly different between groups. Our studies show that KNDy neurons are essential for tonic levels of serum LH and estrous cyclicity and may play a role in limiting the magnitude of the LH surge.

Original languageEnglish (US)
Pages (from-to)2015-2027
Number of pages13
JournalEndocrinology
Volume157
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Hypogonadism
Steroids
Neurons
Arcuate Nucleus of Hypothalamus
Neurokinin B
Kisspeptins
Periodicity
Gonadotropin-Releasing Hormone
Atrophy
Progesterone
Estradiol
Neurokinin-3 Receptors
Follicular Atresia
Ventral Thalamic Nuclei
Diestrus
Dynorphins
Vaginal Smears
Serum
Ovary
Rodentia

ASJC Scopus subject areas

  • Endocrinology

Cite this

Ablation of KNDy neurons results in hypogonadotropic hypogonadism and amplifies the steroid-induced lh surge in female rats. / Mittelman-Smith, Melinda A.; Krajewski-Hall, Sally J.; McMullen, Nathaniel T.; Rance, Naomi E.

In: Endocrinology, Vol. 157, No. 5, 01.05.2016, p. 2015-2027.

Research output: Contribution to journalArticle

Mittelman-Smith, Melinda A. ; Krajewski-Hall, Sally J. ; McMullen, Nathaniel T. ; Rance, Naomi E. / Ablation of KNDy neurons results in hypogonadotropic hypogonadism and amplifies the steroid-induced lh surge in female rats. In: Endocrinology. 2016 ; Vol. 157, No. 5. pp. 2015-2027.
@article{e07ff681cce44455a0ab5d83c33405ac,
title = "Ablation of KNDy neurons results in hypogonadotropic hypogonadism and amplifies the steroid-induced lh surge in female rats",
abstract = "In the human infundibular (arcuate) nucleus, a subpopulation of neurons coexpress kisspeptin and neurokinin B (NKB), 2 peptides required for normal reproductive function. A homologous group of neurons exists in the arcuate nucleus of rodents, termed KNDy neurons based on the coexpression of kisspeptin, NKB, and dynorphin. To study their function,werecently developed a method to selectively ablate KNDy neurons using NK3-SAP, a neurokinin 3 receptor agonist conjugated to saporin (SAP). Here, we ablated KNDy neurons in female rats to determine whether these neurons are required for estrous cyclicity and the steroid induced LH surge. NK3-SAP or Blank-SAP (control) was microinjected into the arcuate nucleus using stereotaxic surgery. After monitoring vaginal smears for 3-4 weeks, rats were ovariectomized and given 17-estradiol and progesterone in a regimen that induced an afternoon LH surge. Rats were killed at the time of peak LH levels, and brains were harvested for NKB and dual labeled GnRH/Fos immunohistochemistry. In ovary-intact rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, characterized by low levels of serum LH, constant diestrus, ovarian atrophy with increased follicular atresia, and uterine atrophy. Surprisingly, the 17-estradiol and progesterone-induced LH surge was 3 times higher in KNDy-ablated rats. Despite the marked increase in the magnitude of the LH surge, the number of GnRH or anterior ventral periventricular nucleus neurons expressing Fos was not significantly different between groups. Our studies show that KNDy neurons are essential for tonic levels of serum LH and estrous cyclicity and may play a role in limiting the magnitude of the LH surge.",
author = "Mittelman-Smith, {Melinda A.} and Krajewski-Hall, {Sally J.} and McMullen, {Nathaniel T.} and Rance, {Naomi E}",
year = "2016",
month = "5",
day = "1",
doi = "10.1210/en.2015-1740",
language = "English (US)",
volume = "157",
pages = "2015--2027",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "5",

}

TY - JOUR

T1 - Ablation of KNDy neurons results in hypogonadotropic hypogonadism and amplifies the steroid-induced lh surge in female rats

AU - Mittelman-Smith, Melinda A.

AU - Krajewski-Hall, Sally J.

AU - McMullen, Nathaniel T.

AU - Rance, Naomi E

PY - 2016/5/1

Y1 - 2016/5/1

N2 - In the human infundibular (arcuate) nucleus, a subpopulation of neurons coexpress kisspeptin and neurokinin B (NKB), 2 peptides required for normal reproductive function. A homologous group of neurons exists in the arcuate nucleus of rodents, termed KNDy neurons based on the coexpression of kisspeptin, NKB, and dynorphin. To study their function,werecently developed a method to selectively ablate KNDy neurons using NK3-SAP, a neurokinin 3 receptor agonist conjugated to saporin (SAP). Here, we ablated KNDy neurons in female rats to determine whether these neurons are required for estrous cyclicity and the steroid induced LH surge. NK3-SAP or Blank-SAP (control) was microinjected into the arcuate nucleus using stereotaxic surgery. After monitoring vaginal smears for 3-4 weeks, rats were ovariectomized and given 17-estradiol and progesterone in a regimen that induced an afternoon LH surge. Rats were killed at the time of peak LH levels, and brains were harvested for NKB and dual labeled GnRH/Fos immunohistochemistry. In ovary-intact rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, characterized by low levels of serum LH, constant diestrus, ovarian atrophy with increased follicular atresia, and uterine atrophy. Surprisingly, the 17-estradiol and progesterone-induced LH surge was 3 times higher in KNDy-ablated rats. Despite the marked increase in the magnitude of the LH surge, the number of GnRH or anterior ventral periventricular nucleus neurons expressing Fos was not significantly different between groups. Our studies show that KNDy neurons are essential for tonic levels of serum LH and estrous cyclicity and may play a role in limiting the magnitude of the LH surge.

AB - In the human infundibular (arcuate) nucleus, a subpopulation of neurons coexpress kisspeptin and neurokinin B (NKB), 2 peptides required for normal reproductive function. A homologous group of neurons exists in the arcuate nucleus of rodents, termed KNDy neurons based on the coexpression of kisspeptin, NKB, and dynorphin. To study their function,werecently developed a method to selectively ablate KNDy neurons using NK3-SAP, a neurokinin 3 receptor agonist conjugated to saporin (SAP). Here, we ablated KNDy neurons in female rats to determine whether these neurons are required for estrous cyclicity and the steroid induced LH surge. NK3-SAP or Blank-SAP (control) was microinjected into the arcuate nucleus using stereotaxic surgery. After monitoring vaginal smears for 3-4 weeks, rats were ovariectomized and given 17-estradiol and progesterone in a regimen that induced an afternoon LH surge. Rats were killed at the time of peak LH levels, and brains were harvested for NKB and dual labeled GnRH/Fos immunohistochemistry. In ovary-intact rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, characterized by low levels of serum LH, constant diestrus, ovarian atrophy with increased follicular atresia, and uterine atrophy. Surprisingly, the 17-estradiol and progesterone-induced LH surge was 3 times higher in KNDy-ablated rats. Despite the marked increase in the magnitude of the LH surge, the number of GnRH or anterior ventral periventricular nucleus neurons expressing Fos was not significantly different between groups. Our studies show that KNDy neurons are essential for tonic levels of serum LH and estrous cyclicity and may play a role in limiting the magnitude of the LH surge.

UR - http://www.scopus.com/inward/record.url?scp=84969802737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84969802737&partnerID=8YFLogxK

U2 - 10.1210/en.2015-1740

DO - 10.1210/en.2015-1740

M3 - Article

C2 - 26937713

AN - SCOPUS:84969802737

VL - 157

SP - 2015

EP - 2027

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 5

ER -