The Connection Between Relaxin And Possible Height Increase

Me: Ever since we started to find stories and posts on the internet mothering and pregnancy boards where women have come forward to state that their height increase from their pregnancy, the topic of relaxin as a possible height increase hormone has been raised. Tyler has recently done a post on the subject (link HERE).

Tyler: Added a new study directly below.  The most likely cause of the pregnancy height gain some females experience is due to increase in tendon length as there doesn’t seem to be any logical connection between relaxin and longitudinal bone growth.  Although the cattle pelvic height growth study seems to indicate that relaxin could somehow induce articular cartilage endochondral ossification results in pelvic height growth.

The effect of relaxin on the musculoskeletal system.

“Relaxin circulates during pregnancy emanating from the corpus luteum and placenta”

“In rodents, circulating relaxin peak concentrations at the end of pregnancy reach 100 ng/mL, two times greater than in human”

“seven known relaxin family peptides (RXFP) are structurally related to insulin which include relaxin (RLN)1, RLN2, RLN3, and insulin-like peptide (INSL)3, INSL4, INSL5, and INSL6″

” Relaxin alters cartilage and tendon stiffness by activating collagenase”

The study notes that Relaxin increases length in cartilage and tendons(Fig 2).

Relaxin has a role in osteoclastgenesis.

“Relaxin treatment in pregnant cattle increased pelvic width and height, but not in other joints such as wrist and knee”

“Relaxin appears to decrease knee articular cartilage stiffness through induction of collagenase-1, MMP-1, and MMP-3, which reduces collagen content and expression in fibrocartilaginous cells. Modulation of MMPs to loss of collagen by hormones may contribute selectively to degeneration of specific joints fibrocartilaginous explants facilitated by proteinases. The degradation of extracellular matrix in fibrocartilage is synergized by β-estradiol. Relaxin exerts its effect through binding to RXFP1 and RXFP2 receptors. The ratio of RXFP2 in knee meniscus of pregnant rabbits was shown to be more than RXFP1, which may indicate differential role of these receptors in the remodeling of fibrocartilage. Comparison of collagen content in articular cartilage of nonpregnant and pregnant rabbits showed that the total RNA levels and chondrocyte metabolism decreased during pregnancy.”

One study has noted that porcine relaxin is capable of modifying type II collagen expression in chondrocyte cells.  Another study found that relaxin increased tendon length so tendon length could be related to the height grain in pregnancy.

This is my attempt in trying to see whether any PubMd studies I have found would be worth mentioning in relevance to our research. I would cite and copy below 5 studies.

Analysis & Interpretation:

From the 1st study…

I would assume Tyler in his post used the study “Pelvic development as affected by relaxin in three genetically selected frame sizes of beef heifers”. The really interesting thing is that the study seems to show that the entire pelvic bone area increased in size. The term “primiparous beed heifers” refer to female cows which are going through their first birthing experience. The issue with the study is of course that cows were used than humans. Also it doesn’t really go and try to explain how it was possible that relaxin caused the increase in pelvic height increase or pelvic width increase. I am now cow expert so I don’t know whether the cows were still growing by the standards of humans. What I do know is that cows which are going through their first birthing experience can easily be young enough to still have growth plate cartilage so what we see in pelvic bone height can be just the excess release of whatever hormones female cows will go through when they are pregnant. From the controlled study we see that relaxin being introduced does cause clear increases in pelvic bone height and width.

For humans, we have to remember the way human female reproductive systems work. The indication that human females can grow is from the start of the menses cycle. The first menses is known as the menarche. Most girls would have their menarche during the puberty stage, but before the growth plates ossify completely. This means that before girls stop growing taller, they would develop the ability to have children and go through the human gestation process. In bovine, we would guess it is the same thing. In conclusion, from just this one study we can see that in cows, the hormone relaxin has the ability to increase pelvic height. Since the pelvic bone outline/structure does indeed contribute to the overall human height, the increase in pelvic height we see in young female bovine may be able to be translated to young human females. However the age values we find from the internet discussion boards and forum suggest that the relaxin is doing something more exordinary since the women are already even in their late 20s or 30s when they notice the height increase. If relaxin is just only a muscle relaxant, how does it actually make pelvic bone taller? Just something to wonder about right now.

{Tyler: “Pelvic height was determined by measuring the linear distance from the approximate midpoint of the dorsal surface of the symphysis pubis to the ventral surface of the prominent junction of the third and fourth segments of the sacral vertebrae”<-Doesn’t seem to factor in tendon length.

“pelvic growth during the last 10 days before parturition[child birth] can be modified by the intracervical administration of relaxin.”

“The mechanism of pelvic canal expansion in cattle is unknown. The pelvic canal may increase in area as a result of relaxation of sacroiliac ligaments, formation of interpubic ligaments, and modification of the pubic symphysis by transforming symphyseal cartilage[a type of cartilage joint] and bone{if it does this then relaxin could have very strong height increase potential}“<-growing from the pubic symphysis would be like growing from the articular cartilage which would have very nice height increase implications.  The study that discsusses this is called Dystocia in Cattle by LE Rice unfortunately I could not find this study.

From the 2nd study…

If we however look at the 2nd study I have linked, we can see that Relaxin, specifically the Relaxin Family Peptide Receptor 1 (RXFP1) can be the precursor to a mechanism which triggers many of the other pathways and hormones we have looked at before. including NO and cGMP. Somehow it disrupts the TGF-β1/Smad2 axis through a signal process that involves the ERK/pERK/NO/cGMP pahway. One set of proteins I have been trying to get to researching more into are the MMPs. Somehow the RXFP1 increase matrix metalloproteinase (MMP) expression. My knowledge on MMPs are nonexistent at this point so I can’t really breakdown what the abstract is really talking about. However the researchers would conclude with…

“These findings demonstrated that H2 relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to mediate its anti-fibrotic actions, and additionally signals through iNOS to up-regulate MMPs; the latter being suppressed by TGF-β1 in myofibroblasts, but released upon H2 relaxin-induced inhibition of the TGF-β1/Smad2 axis”

So I guess the two main things to take away from this study is that the H2 relaxin seems to inhibit/suppress the differentiation of myofibroblast and also increase the gene expression of the MMPs.

From the 3rd study…

Relaxin seems to regulate the expression of two types of MMPs, MMP-9 and MMP-13. Relaxin is a type of ligand that attaches to a certain type of substrate or receptor which will accept it. There is two types of relaxin receptors described in this study, Relaxin family peptide receptors 1 & 2, called RXFP1 & RXFP2 respectively. It would seem that the RXFP1 is the one that has the real regulating power on MMP9 & MMP-13 expression while the RXFP2 doesn’t seem to regulate the MMP expression. There are quite a few pathways involved in the relaxin’s regulating ability including the PI3K, AKT, ERK, and a few other pathways or compounds which I am not familiar with at this time. The main thing to take away from this study is that relaxin has some regulating ability over the extracellular matrix and MMP expression.

From the 4th study…

From the 3rd study we learn that there seems to be at least two main relaxin receptors, called the relaxin family peptide receptors, RXFP1 and RXFP2. It seems that while the first receptor RXFP1 is for the actual relaxin compound in a ligand-substrate match, the 2nd receptor is for matching with something called insulin like peptide (INSL)3. Both of the receptors and thus both of the compounds increase the cAMP level but through two different pathways, also both going through a compound called a G-Alpha. At this point I don’t understand or know what most of the abstract is talking about but the key to understand is that the relaxin and another compound very similar to it both increases cAMP expression. Like what we find in the 2nd and 3rd studies, relaxin can increase the up-regulation of a few key compounds which we have looked at before in our research.

From the 5th study…

It would seem that this compound we have been looking at through the last 5 studies is well known as a an anti-fibrotic element. It is a peptide hormone that inhibits fibrosis of different types, but for this study specifically the cardiac fibrosis type. When you take TGF-Beta or Angiotensin Type II (Ang II) it would cause accelerated fibroblast differentiation into myofibroblasts. Relaxin seems to inhibit the differentiation of fibroblasts which are treated with Ang II, IGF-1, or TGF-beta. This was found from detecting that the expression of alpha-smooth muscle actin and collagen decreased. MMP-2 expression was also noted to have increased from relaxin under the presence of the Angiotensin II and TGF-beta.

The researchers would conclude with…

“These coherent findings indicate that relaxin regulates fibroblast proliferation, differentiation, and collagen deposition and may have therapeutic potential in diseased states characterized by cardiac fibrosis”


At this point, I would say that relaxin is something that I would need to study further since it and it’s receptors the RXFP1 and RXFP2 have some regulating function towards many types of the MMPs, MMP2, 9, and 13. It also have control over the expression of cAMP and fibroblast differentiation ability.

Biol Reprod. 1986 Mar;34(2):363-9.

Pelvic development as affected by relaxin in three genetically selected frame sizes of beef heifers.

Musah AI, Schwabe C, Willham RL, Anderson LL.


Purified porcine relaxin was administered into the cervical os on Day 278 of gestation to determine its effects on pelvic development in three genetically selected frame sizes of primiparous beef heifers. Heifers were categorized as small, medium and large frame based upon their genetic composition. Pelvic height, pelvic width and cervical dilatation were determined from Day 270 to 2 days postpartum. On Day 270, heifers were assigned at random to one of three treatments: vehicle control, n = 16; relaxin once (3,000 U), n = 14; and relaxin twice (2 times 3,000 U 12 h apart), n = 17. Each heifer-frame size was represented in each treatment. Relaxin caused marked increases in pelvic height and width, as well as in the rate of linear increase (cm/day) of these parameters (p less than 0.05). These linear increases in pelvic height were 510, 264 and 204%, and pelvic width, were 280, 213 and 204% of the respective pretreatment rates for small, medium and large heifers. The rate of linear increase in pelvic width was greater than pelvic height in all heifers, but maximal in small-frame heifers; relaxin attenuated these intrinsic differences. For small heifers, the rate of linear increase in pelvic width was 121 and 145% of increases for medium and large heifers, respectively, before treatment, and 160 and 200% after treatment. The rate of postpartum involution of pelvic width was -0.03, -0.36 and -0.50 cm/day and, for pelvic height, -0.02, -0.27 and -0.29 cm/day in small, medium and large heifers, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 3955148     [PubMed – indexed for MEDLINE]    Free full text

From PubMed study 2 link HERE

PLoS One. 2012;7(8):e42714. doi: 10.1371/journal.pone.0042714. Epub 2012 Aug 22.
Relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to up-regulate matrix metalloproteinases: the additional involvement of iNOS.
Chow BS, Chew EG, Zhao C, Bathgate RA, Hewitson TD, Samuel CS.

Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria, Australia.


The hormone, relaxin, inhibits aberrant myofibroblast differentiation and collagen deposition by disrupting the TGF-β1/Smad2 axis, via its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1), extracellular signal-regulated kinase (ERK)1/2 phosphorylation (pERK) and a neuronal nitric oxide (NO) synthase (nNOS)-NO-cyclic guanosine monophosphate (cGMP)-dependent pathway. However, the signalling pathways involved in its additional ability to increase matrix metalloproteinase (MMP) expression and activity remain unknown. This study investigated the extent to which the NO pathway was involved in human gene-2 (H2) relaxin’s ability to positively regulate MMP-1 and its rodent orthologue, MMP-13, MMP-2 and MMP-9 (the main collagen-degrading MMPs) in TGF-β1-stimulated human dermal fibroblasts and primary renal myofibroblasts isolated from injured rats; by gelatin zymography (media) and Western blotting (cell layer). H2 relaxin (10-100 ng/ml) significantly increased MMP-1 (by ~50%), MMP-2 (by ~80%) and MMP-9 (by ~80%) in TGF-β1-stimulated human dermal fibroblasts; and MMP-13 (by ~90%), MMP-2 (by ~130%) and MMP-9 (by ~115%) in rat renal myofibroblasts (all p<0.01 vs untreated cells) over 72 hours. The relaxin-induced up-regulation of these MMPs, however, was significantly blocked by a non-selective NOS inhibitor (L-nitroarginine methyl ester (hydrochloride); L-NAME; 75-100 µM), and specific inhibitors to nNOS (N-propyl-L-arginine; NPLA; 0.2-2 µM), iNOS (1400W; 0.5-1 µM) and guanylyl cyclase (ODQ; 5 µM) (all p<0.05 vs H2 relaxin alone), but not eNOS (L-N-(1-iminoethyl)ornithine dihydrochloride; L-NIO; 0.5-5 µM). However, neither of these inhibitors affected basal MMP expression at the concentrations used. Furthermore, of the NOS isoforms expressed in renal myofibroblasts (nNOS and iNOS), H2 relaxin only stimulated nNOS expression, which in turn, was blocked by the ERK1/2 inhibitor (PD98059; 1 µM). These findings demonstrated that H2 relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to mediate its anti-fibrotic actions, and additionally signals through iNOS to up-regulate MMPs; the latter being suppressed by TGF-β1 in myofibroblasts, but released upon H2 relaxin-induced inhibition of the TGF-β1/Smad2 axis.

PMID: 22936987 [PubMed – in process] PMCID: PMC3425563

From PubMed study 3 link HERE

Mol Cell Endocrinol. 2012 Nov 5;363(1-2):46-61. doi: 10.1016/j.mce.2012.07.006. Epub 2012 Jul 24.
Relaxin induces matrix-metalloproteinases-9 and -13 via RXFP1: Induction of MMP-9 involves the PI3K, ERK, Akt and PKC-ζ pathways.
Ahmad N, Wang W, Nair R, Kapila S.

The University of Michigan, 1011 North University Avenue, Ann Arbor, MI 48109-1078, USA.


We determined the precise role of relaxin family peptide (RXFP) receptors-1 and -2 in the regulation of MMP-9 and -13 by relaxin, and delineated the signaling cascade that contributes to relaxin’s modulation of MMP-9 in fibrocartilaginous cells. Relaxin treatment of cells in which RXFP1 was silenced resulted in diminished induction of MMP-9 and -13 by relaxin, whereas overexpression of RXFP1 potentiated the relaxin-induced expression of these proteinases. Suppression or overexpression of RXFP2 resulted in no changes in the relaxin-induced MMP-9 and -13. Studies using chemical inhibitors and siRNAs to signaling molecules showed that PI3K, Akt, ERK and PKC-ζ and the transcription factors Elk-1, c-fos and, to a lesser extent, NF-κB are involved in relaxin’s induction of MMP-9. Our findings provide the first characterization of signaling cascade involved in the regulation of any MMP by relaxin and offer mechanistic insights on how relaxin likely mediates extracellular matrix turnover.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

PMID:  22835547     [PubMed – in process] 

From PubMed study 4 link HERE

Mol Pharmacol. 2006 Jul;70(1):214-26. Epub 2006 Mar 28.
Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms.
Halls ML, Bathgate RA, Summers RJ.

Department of Pharmacology, P.O. Box 13E, Monash University, Clayton, VIC 3800, Australia.


Two orphan leucine-rich repeat-containing G protein-coupled receptors were recently identified as targets for the relaxin family peptides relaxin and insulin-like peptide (INSL) 3. Human gene 2 relaxin is the cognate ligand for relaxin family peptide receptor (RXFP) 1, whereas INSL3 is the ligand for RXFP2. Constitutively active mutants of both receptors when expressed in human embryonic kidney (HEK) 293T cells signal through Galphas to increase cAMP. However, recent studies using cells that endogenously express the receptors revealed greater complexity: cAMP accumulation after activation of RXFP1 involves a time-dependent biphasic pathway with a delayed phase involving phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) zeta, whereas the RXFP2 response involves inhibition of adenylate cyclase via pertussis toxin-sensitive G proteins. The aim of this study was to compare and contrast the cAMP signaling pathways used by these two related receptors. In HEK293T cells stably transfected with RXFP1, preliminary studies confirmed the biphasic cAMP response, with an initial Galphas component and a delayed response involving PI3K and PKCzeta. This delayed pathway was dependent upon G-betagamma subunits derived from Galphai3. An additional inhibitory pathway involving GalphaoB affecting cAMP accumulation was also identified. In HEK293T cells stably transfected with RXFP2, the cAMP response involved Galphas and was modulated by inhibition mediated by GalphaoB and release of inhibitory G-betagamma subunits. Thus, initially both RXFP1 and RXFP2 couple to Galphas and an inhibitory GalphaoB pathway. Differences in cAMP accumulation stem from the ability of RXFP1 to recruit coupling to Galphai3, release G-betagamma subunits and thus activate a delayed PI3K-PKCzeta pathway to further increase cAMP accumulation.

PMID:  16569707   [PubMed – indexed for MEDLINE]      Free full text

From PubMed study 5 link HERE

Endocrinology. 2004 Sep;145(9):4125-33. Epub 2004 May 20.
Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo.
Samuel CS, Unemori EN, Mookerjee I, Bathgate RA, Layfield SL, Mak J, Tregear GW, Du XJ.

Howard Florey Institute, Gate 11, University of Melbourne, Parkville, Victoria 3010, Australia. c.samuel@hfi.unimelb.


Cardiac fibrosis is a key component of heart disease and involves the proliferation and differentiation of matrix-producing fibroblasts. The effects of an antifibrotic peptide hormone, relaxin, in inhibiting this process were investigated. We used rat atrial and ventricular fibroblasts, which respond to profibrotic stimuli and express the relaxin receptor (LGR7), in addition to two in vivo models of cardiac fibrosis. Cardiac fibroblasts, when plated at low density or stimulated with TGF-beta or angiotensin II (Ang II), accelerated fibroblast differentiation into myofibroblasts, as demonstrated by significantly increased alpha-smooth muscle actin expression, collagen synthesis, and collagen deposition (by up to 95% with TGF-beta and 40% with Ang II; all P < 0.05). Fibroblast proliferation was significantly increased by 10(-8) m and 10(-7) m Ang II (63-75%; P < 0.01) or 0.1-1 microg/ml IGF-I (27-40%; P < 0.05). Relaxin alone had no marked effect on these parameters, but it significantly inhibited Ang II- and IGF-I-mediated fibroblast proliferation (by 15-50%) and Ang II- and TGF-beta-mediated fibroblast differentiation, as detected by decreased expression of alpha-smooth muscle actin (by 65-88%) and collagen (by 60-80%). Relaxin also increased matrix metalloproteinase-2 expression in the presence of TGF-beta (P < 0.01) and Ang II (P < 0.05). Furthermore, relaxin decreased collagen overexpression when administered to two models of established fibrotic cardiomyopathy, one due to relaxin deficiency (by 40%; P < 0.05) and the other to cardiac-restricted overexpression of beta2-adrenergic receptors (by 58%; P < 0.01). These coherent findings indicate that relaxin regulates fibroblast proliferation, differentiation, and collagen deposition and may have therapeutic potential in diseased states characterized by cardiac fibrosis.

PMID: 15155573    [PubMed – indexed for MEDLINE]       Free full text

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