CoChat
Sign Up
Cited by 12Hypothalamic control of reproductive hormonesNeuroendocrine regulation and behaviorRegulation of Appetite and Obesity

Prolactin-mediates a lactation-induced suppression of arcuate kisspeptin neuronal activity necessary for lactational infertility in mice

Open access
Hackwell, Eleni CR, Ladyman, Sharon R, Clarkson, Jenny, McQuillan, H James, Boehm, Ulrich, Herbison, Allan E, Brown, Rosemary SE, Grattan, David R·2025·eLife
DOI 10.7554/elife.94570PMC PMC11741520

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

The specific role that prolactin plays in lactational infertility, as distinct from other suckling or metabolic cues, remains unresolved. Here, deletion of the prolactin receptor (Prlr) from forebrain neurons or arcuate kisspeptin neurons resulted in failure to maintain normal lactation-induced suppression of estrous cycles. Kisspeptin immunoreactivity and pulsatile LH secretion were increased in these mice, even in the presence of ongoing suckling stimulation and lactation. GCaMP fibre photometry of arcuate kisspeptin neurons revealed that the normal episodic activity of these neurons is rapidly suppressed in pregnancy and this was maintained throughout early lactation. Deletion of Prlr from arcuate kisspeptin neurons resulted in early reactivation of episodic activity of kisspeptin neurons prior to a premature return of reproductive cycles in early lactation. These observations show dynamic variation in arcuate kisspeptin neuronal activity associated with the hormonal changes of pregnancy and lactation, and provide direct evidence that prolactin action on arcuate kisspeptin neurons is necessary for suppressing fertility during lactation in mice.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.7554/elife.94570

Cites

13 of 13 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A perfect correlation exists between ARNKISS neuron SEs and LH pulses in all physiological and pathophysiological conditions examined to date.

    “A perfect correlation exists between ARNKISS neuron SEs and LH pulses in all physiological and pathophysiological conditions examined to date7–11.”

    From Brainstem noradrenergic modulation of the kisspeptin neuron GnRH pulse generator in mice (2025) · cites this paper as [11]

    Figure 4 in the Results reports a 100% correspondence in the paired recordings: all 73 observed arcuate kisspeptin neuron SEs were followed by an LH pulse. That finding supports the correlation, but it is bounded by the reproductive states examined in Kiss1Cre mice; the paper does not establish a perfect correlation across all physiological and pathophysiological conditions examined to date. No page number is available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 62

  1. Bohnet HG Schneider HP 1977 Prolactin as a cause of anovulation Crosignani PG Robyn C Prolactin and Human Reproduction Academic Press 153 159
  2. Bridges RS 1984 A quantitative analysis of the roles of dosage, sequence, and duration of estradiol and progesterone exposure in the regulation of maternal behavior in the rat Endocrinology 114 930 940 10.1210/endo-114-3-930 6697968 · DOI
  3. Briski KP Sylvester PW 1987 Effects of sequential acute stress exposure on stress-induced pituitary luteinizing hormone and prolactin secretion Life Sciences 41 1249 1255 10.1016/0024-3205(87)90203-7 3626756 · DOI
  4. Brown RSE Herbison AE Grattan DR 2014 Prolactin regulation of kisspeptin neurones in the mouse brain and its role in the lactation-induced suppression of kisspeptin expression Journal of Neuroendocrinology 26 898 908 10.1111/jne.12223 25207795 · DOI
  5. Brown RSE Kokay IC Phillipps HR Yip SH Gustafson P Wyatt A Larsen CM Knowles P Ladyman SR LeTissier P Grattan DR 2016 Conditional deletion of the prolactin receptor reveals functional subpopulations of dopamine neurons in the arcuate nucleus of the hypothalamus Journal of Neuroscience 36 9173 9185 10.1523/JNEUROSCI.1471-16.2016 27581458 PMC6601914 · DOI
  6. Brown RSE Khant Aung Z Phillipps HR Barad Z Lein HJ Boehm U Szawka RE Grattan DR 2019 Acute Suppression of LH secretion by prolactin in female mice is mediated by kisspeptin neurons in the arcuate nucleus Endocrinology 160 1323 1332 10.1210/en.2019-00038 30901026 · DOI · Paper page
  7. Clarkson J Boon WC Simpson ER Herbison AE 2009a Postnatal development of an estradiol-kisspeptin positive feedback mechanism implicated in puberty onset Endocrinology 150 3214 3220 10.1210/en.2008-1733 19299459 PMC2703539 · DOI
  8. Clarkson J D’Anglemont de Tassigny X Colledge WH Caraty A Herbison AE 2009b Distribution of kisspeptin neurones in the adult female mouse brain Journal of Neuroendocrinology 21 673 682 10.1111/j.1365-2826.2009.01892.x 19515163 · DOI · Paper page
  9. Cohen-Becker IR Selmanoff M Wise PM 1986 Hyperprolactinemia alters the frequency and amplitude of pulsatile luteinizing hormone secretion in the ovariectomized rat Neuroendocrinology 42 328 333 10.1159/000124459 3515222 · DOI
  10. Czieselsky K Prescott M Porteous R Campos P Clarkson J Steyn FJ Campbell RE Herbison AE 2016 Pulse and surge profiles of luteinizing hormone secretion in the mouse Endocrinology 157 4794 4802 10.1210/en.2016-1351 27715255 · DOI
  11. de Roux N Genin E Carel J-C Matsuda F Chaussain J-L Milgrom E 2003 Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 PNAS 100 10972 10976 10.1073/pnas.1834399100 12944565 PMC196911 · DOI · Paper page
  12. Díaz S Serón-Ferré M Cárdenas H Schiappacasse V Brandeis A Croxatto HB 1989 Circadian variation of basal plasma prolactin, prolactin response to suckling, and length of amenorrhea in nursing women The Journal of Clinical Endocrinology and Metabolism 68 946 955 10.1210/jcem-68-5-946 2715293 · DOI
  13. Evans W Cronin M Thorner M 1982 Hypoganadism in hyperprolactinemia: proposed mechanisms J Clin Invert 122 3467 3468 10.1172/JCI64455 · DOI
  14. Fox SR Smith MS 1984 The suppression of pulsatile luteinizing hormone secretion during lactation in the rat* Endocrinology 115 2045 2051 10.1210/endo-115-6-2045 6389094 · DOI
  15. Goodman RL Karsch FJ 1980 Pulsatile secretion of luteinizing hormone: differential suppression by ovarian steroids Endocrinology 107 1286 1290 10.1210/endo-107-5-1286 7000489 · DOI
  16. Greer ME Moraczewski T Rakoff JS 1980 Prevalence of hyperprolactinemia in anovulatory women Obstetrics and Gynecology 56 65 69 7189848
  17. Gustafson P Ladyman SR McFadden S Larsen C Khant Aung Z Brown RSE Bunn SJ Grattan DR 2020 Prolactin receptor-mediated activation of pSTAT5 in the pregnant mouse brain Journal of Neuroendocrinology 32 e12901 10.1111/jne.12901 33000513 · DOI
  18. Hackwell ECR Ladyman SR Brown RSE Grattan DR 2023 Mechanisms of lactation-induced infertility in female mice Endocrinology 164 bqad049 10.1210/endocr/bqad049 36960565 PMC10083203 · DOI
  19. Han SY Morris PG Kim JC Guru S Pardo-Navarro M Yeo SH McQuillan HJ Herbison AE 2023 Mechanism of kisspeptin neuron synchronization for pulsatile hormone secretion in male mice Cell Reports 42 111914 10.1016/j.celrep.2022.111914 36640343 PMC7618808 · DOI · Paper page
  20. Henderson HL Townsend J Tortonese DJ 2008 Direct effects of prolactin and dopamine on the gonadotroph response to GnRH The Journal of Endocrinology 197 343 350 10.1677/JOE-07-0536 18434364 · DOI
  21. Hodson DJ Townsend J Tortonese DJ 2010 Characterization of the effects of prolactin in gonadotroph target cells Biology of Reproduction 83 1046 1055 10.1095/biolreprod.110.084947 20720166 · DOI
  22. Kim CK Yang SJ Pichamoorthy N Young NP Kauvar I Jennings JH Lerner TN Berndt A Lee SY Ramakrishnan C Davidson TJ Inoue M Bito H Deisseroth K 2016 Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain Nature Methods 13 325 328 10.1038/nmeth.3770 26878381 PMC5717315 · DOI
  23. Koike K Miyake A Aono T Sakumoto T Ohmichi M Yamaguchi M Tanizawa O 1991 Effect of prolactin on the secretion of hypothalamic GnRH and pituitary gonadotropins Hormone Research 35 Suppl 1 5 12 10.1159/000181921 1752606 · DOI
  24. Ladyman SR Woodside B 2014 Food restriction during lactation suppresses Kiss1 mRNA expression and kisspeptin-stimulated LH release in rats Rrproduction 147 743 751 10.1530/REP-13-0426 24492858 · DOI
  25. Liu X Herbison AE 2013 Dopamine regulation of gonadotropin-releasing hormone neuron excitability in male and female mice Endocrinology 154 340 350 10.1210/en.2012-1602 23239814 · DOI
  26. Liu X Brown RSE Herbison AE Grattan DR 2014 Lactational anovulation in mice results from a selective loss of kisspeptin input to GnRH neurons Endocrinology 155 193 203 10.1210/en.2013-1621 24169550 · DOI
  27. Maeda K Uchida E Tsukamura H Ohkura N Ohkura S Yokoyama A 1990 Prolactin does not mediate the suppressive effect of the suckling stimulus on luteinizing hormone secretion in ovariectomized lactating rats Endocrinologia Japonica 37 405 411 10.1507/endocrj1954.37.405 2253591 · DOI
  28. McNeilly AS 1979 Effects of lactation on fertility British Medical Bulletin 35 151 154 10.1093/oxfordjournals.bmb.a071562 387162 · DOI
  29. McNeilly AS Glasier AF Howie PW Houston MJ Cook A Boyle H 1983 Fertility after childbirth: pregnancy associated with breast feeding Clinical Endocrinology 19 167 173 10.1111/j.1365-2265.1983.tb02978.x 6883735 · DOI
  30. McNeilly AS 1994 Suckling and the control of gonadotropin secretion McNeilly AS Knobil and Neill’s Physiology of Reproduction Elsevier 2511 2551
  31. McNeilly AS Tay CC Glasier A 1994 Physiological mechanisms underlying lactational amenorrhea Annals of the New York Academy of Sciences 709 145 155 10.1111/j.1749-6632.1994.tb30394.x 8154698 · DOI
  32. McNeilly AS 1997 Lactation and fertility Journal of Mammary Gland Biology and Neoplasia 2 291 298 10.1023/a:1026340606252 10882312 · DOI
  33. McNeilly AS 2001 Lactational control of reproduction Reproduction, Fertility, and Development 13 583 590 10.1071/rd01056 11999309 · DOI
  34. Morishige WK Pepe GJ Rothchild I 1973 Serum luteinizing hormone, prolactin and progesterone levels during pregnancy in the rat Endocrinology 92 1527 1530 10.1210/endo-92-5-1527 4695432 · DOI
  35. Moult PJ Rees LH Besser GM 1982 Pulsatile gonadotrophin secretion in hyperprolactinaemic amenorrhoea an the response to bromocriptine therapy Clinical Endocrinology 16 153 162 10.1111/j.1365-2265.1982.tb03159.x 6802531 · DOI
  36. Ördög T Chen M-D O’Byrne KT Goldsmith JR Connaughton MA Hotchkiss J Knobil E 1998 On the mechanism of lactational anovulation in the rhesus monkey American Journal of Physiology-Endocrinology and Metabolism 274 E665 E676 10.1152/ajpendo.1998.274.4.E665 9575828 · DOI · Paper page
  37. Park SK Selmanoff M 1991 Dose-dependent suppression of postcastration luteinizing hormone secretion exerted by exogenous prolactin administration in male rats: a model for studying hyperprolactinemic hypogonadism Neuroendocrinology 53 404 410 10.1159/000125748 2046873 · DOI
  38. Park SK Keenan MW Selmanoff M 1993 Graded hyperprolactinemia first suppresses LH pulse frequency and then pulse amplitude in castrated male rats Neuroendocrinology 58 448 453 10.1159/000126575 8284029 · DOI
  39. Patel SS Bamigboye V 2007 Hyperprolactinaemia Journal of Obstetrics and Gynaecology 27 455 459 10.1080/01443610701406125 17701788 · DOI
  40. Pointis G Rao B Latreille MT Mignot TM Cedard L 1981 Progesterone levels in the circulating blood of the ovarian and uterine veins during gestation in the mouse Biology of Reproduction 24 801 805 10.1095/biolreprod24.4.801 7248413 · DOI
  41. Porteous R Haden P Hackwell ECR Singline A Herde MK Desai R Handelsman DJ Grattan DR Herbison AE 2021 Reformulation of PULSAR for analysis of pulsatile LH secretion and a revised model of estrogen-negative feedback in mice Endocrinology 162 bqab165 10.1210/endocr/bqab165 34383026 · DOI
  42. Roa J Vigo E Castellano JM Navarro VM Fernández-Fernández R Casanueva FF Dieguez C Aguilar E Pinilla L Tena-Sempere M 2006 Hypothalamic Expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female rat Endocrinology 147 2864 2878 10.1210/en.2005-1463 16527840 · DOI
  43. Rolland R Lequin RM Schellekens LA de Jong FH 1975 The role of prolactin in the restoration of ovarian function during the early post-partum period in the human female. I. A study during physiological lactation Clinical Endocrinology 4 15 25 10.1111/j.1365-2265.1975.tb03300.x 1122651 · DOI
  44. Sarkar DK Yen SS 1985 Hyperprolactinemia decreases the luteinizing hormone-releasing hormone concentration in pituitary portal plasma: a possible role for beta-endorphin as a mediator Endocrinology 116 2080 2084 10.1210/endo-116-5-2080 3157564 · DOI
  45. Seminara SB Messager S Chatzidaki EE Thresher RR Acierno JS Jr Shagoury JK Bo-Abbas Y Kuohung W Schwinof KM Hendrick AG Zahn D Dixon J Kaiser UB Slaugenhaupt SA Gusella JF O’Rahilly S Carlton MBL Crowley WF Jr Aparicio SAJR Colledge WH 2003 The GPR54 gene as a regulator of puberty The New England Journal of Medicine 349 1614 1627 10.1056/NEJMoa035322 14573733 · DOI · Paper page
  46. Sherathiya VN Schaid MD Seiler JL Lopez GC Lerner TN 2021 GuPPy, a Python toolbox for the analysis of fiber photometry data Scientific Reports 11 24212 10.1038/s41598-021-03626-9 34930955 PMC8688475 · DOI
  47. Short RV 1976 Lactation--the central control of reproduction Elliott K Fitzsimons DW Ciba Foundation Symposium Wiley 73 86 10.1002/9780470720271.ch5 801808 · DOI
  48. Skinner DC Evans NP Delaleu B Goodman RL Bouchard P Caraty A 1998 The negative feedback actions of progesterone on gonadotropin-releasing hormone secretion are transduced by the classical progesterone receptor PNAS 95 10978 10983 10.1073/pnas.95.18.10978 9724815 PMC28006 · DOI
  49. Smith MS 1978 The relative contribution of suckling and prolactin to the inhibition of gonadotropin secretion during lactation in the rat Biology of Reproduction 19 77 83 10.1095/biolreprod19.1.77 687710 · DOI
  50. Steyn FJ Huang L Ngo ST Leong JW Tan HY Xie TY Parlow AF Veldhuis JD Waters MJ Chen C 2011 Development of a method for the determination of pulsatile growth hormone secretion in mice Endocrinology 152 3165 3171 10.1210/en.2011-0253 21586549 · DOI
  51. Steyn FJ Wan Y Clarkson J Veldhuis JD Herbison AE Chen C 2013 Development of a methodology for and assessment of pulsatile luteinizing hormone secretion in juvenile and adult male mice Endocrinology 154 4939 4945 10.1210/en.2013-1502 24092638 PMC5398599 · DOI
  52. Sugimoto A Tsuchida H Nagae M Inoue N Uenoyama Y Tsukamura H 2022 Central somatostatin-somatostatin receptor 2 signaling mediates lactational suppression of luteinizing hormone release via the inhibition of glutamatergic interneurons during late lactation in rats The Journal of Reproduction and Development 68 190 197 10.1262/jrd.2022-009 35249910 PMC9184827 · DOI
  53. Tay CCK Glasier AF McNeilly AS 1996 Twenty-four hour patterns of prolactin secretion during lactation and the relationship to suckling and the resumption of fertility hi breast-feeding women Human Reproduction 11 950 955 10.1093/oxfordjournals.humrep.a019330 8671369 · DOI
  54. Thapa S Short RV Potts M 1988 Breast feeding, birth spacing and their effects on child survival Nature 335 679 682 10.1038/335679a0 3173491 · DOI
  55. Tortonese DJ Brooks J Ingleton PM McNeilly AS 1998 Detection of prolactin receptor gene expression in the sheep pituitary gland and visualization of the specific translation of the signal in gonadotrophs Endocrinology 139 5215 5223 10.1210/endo.139.12.6365 9832462 · DOI
  56. True C Kirigiti M Ciofi P Grove KL Smith MS 2011 Characterisation of arcuate nucleus kisspeptin/neurokinin B neuronal projections and regulation during lactation in the rat Journal of Neuroendocrinology 23 52 64 10.1111/j.1365-2826.2010.02076.x 21029216 PMC3118985 · DOI
  57. Tsukamura H Maeda K 2001 Non-metabolic and metabolic factors causing lactational anestrus: rat models uncovering the neuroendocrine mechanism underlying the suckling-induced changes in the mother Progress in Brain Research 133 187 205 10.1016/s0079-6123(01)33014-5 11589130 · DOI
  58. Virgo BB Bellward GD 1974 Serum progesterone levels in the pregnant and postpartum laboratory mouse Endocrinology 95 1486 1490 10.1210/endo-95-5-1486 4473330 · DOI
  59. Woodside C Jans JE 1995 Role of the nutritional status of the litter and length and frequency of mother-litter contact bouts in prolonging lactational diestrus in rats Hormones and Behavior 29 154 176 10.1006/hbeh.1995.1012 7557920 · DOI
  60. Xu J Kirigiti MA Grove KL Smith MS 2009 Regulation of food intake and gonadotropin-releasing hormone/luteinizing hormone during lactation: role of insulin and leptin Endocrinology 150 4231 4240 10.1210/en.2009-0190 19470705 PMC2736090 · DOI
  61. Yamada S Uenoyama Y Kinoshita M Iwata K Takase K Matsui H Adachi S Inoue K Maeda KI Tsukamura H 2007 Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats Endocrinology 148 2226 2232 10.1210/en.2006-1529 17289848 · DOI
  62. Zakar T Hertelendy F 2007 Progesterone withdrawal: key to parturition American Journal of Obstetrics and Gynecology 196 289 296 10.1016/j.ajog.2006.09.005 17403397 · DOI

Cited by

Sorted by citations

Authors
Hackwell, E. C., Ladyman, S. R., Clarkson, J., McQuillan, H. J., Boehm, U., Herbison, A. E., Brown, R. S., & Grattan, D. R.
Affiliations
  • University of Otago (NZ)
  • Maurice Wilkins Centre (NZ)
  • Saarland University (DE)
  • University of Cambridge (GB)
Corresponding author
Grattan, David R
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2025-01-17
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.94570
PMC
PMC11741520
OpenAlex
W4392957872
Cited by
12
References
13
Citations by year
2026: 6 · 2025: 4 · 2024: 2
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Health Research Council of New Zealand (21-560)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
prolactin, prolactin receptor, kisspeptin neurons, arcuate nucleus, lactation, luteinizing hormone secretion, pregnancy, neuronal activity, neuroendocrine regulation of reproduction
MeSH terms
Animals, Arcuate Nucleus of Hypothalamus, Female, Infertility, Lactation, Neurons, Pregnancy, Prolactin, Receptors, Prolactin, Estrous Cycle, Mice, Kisspeptins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review