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So I fasted for a few hundred days back in 2014, and I got good at it and it felt good. Like I was doing something good for body and spirit. I started with shortie day fasts, nothing consistent, then kept up the practice and increased to longer fasts -- 3, 4, 5, 7, and I did one 10-day fast.


Then I lost interest.


This year I've returned to fasting -- inspired by Valter Longo, I suppose, but also this guy with an awesome last name. He seems pretty solid:


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I'm on day 6 of a water fast, but I'm about to break it because I'm too dizzy and weak to keep slogging. This is kinda typical fasting behavior for me. I've no prob stopping a fast when my body says stop. Then bounce back. Fasting gets easier with practice. I've read difficulties often relate to the transitions into ketosis and its deeper stages. Once upon a time I monitored this with ketostix but I've lost interest in knowing numbers.


Refeeding is fun. People write to drink or eat sweet fruits, but I do fine with steamed vegetables. I may be too thin already to make fasting a regular priority in my life like I did in 2014. 6'2" and 145 is lean. After six days I'm down to 138, but it's water weight, and I usually pay little attention to weight.


Anyone here fast? It's an interesting practice, and unique way to learn about yourself.

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I stopped fasting at the end of day six -- ate some steamed mushrooms, some broccoli, fancy amphora olive oil, lots of pumpkin seeds, cherries, blueberries. Then I woke up the next morning, wasn't hungry, so thought what the hell, I'll keep fasting. And so I've fasted for three more days -- don't know if that makes nine days or not, but I'm just saying this is day three.


I feel pretty great, finally, after some weak and dizzy days. Getting out of the studio and out into trees really, really helps. Trees energize, especially now, blossoming, oh so beautiful all of them and under that great fragile sky, and clouds forming and dissolving like nothing to birds winging it in from south lands, calling out territories and hey let's fuck, it's spring, my feathers say, let's build a nest, lay some eggs, then those gaping pink mouths to feed and feed, birds are the hardest working of all creatures and also the easiest sailing away into thermals. I'm not sure why I'm fasting or how long I'll go without -- but it feels natural -- and the depression needs to goddamned chill. And I'm tired of moving, contorting my body, twisting across stages for unseen eyeballs, and so doing nothing feels about right.


"When we fast, energy is freed for a thorough housecleaning of the system. The body becomes lighter, more flexible; the mind becomes clearer and more creative. Greater intuitive powers may develop and deep spiritual insights may be experienced after a period of time. A feeling of well-being arises when the energy is freed in this way -- problems suddenly become solutions and ideas flow from nowhere."


Kripalu Center for Holistic Health, from their book The Self-Health Guide

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Hello Sthira, last august I did a 5 days water fasting. I was at my home, no working, I did some taiji and meditation and walking and no other activities. I felt especially weak on the second and third day. In the last two days I had as side effect hiccups. I lost about 1 kg every day

The day after refeeding  my fasting glucose before breakfast arrived at 105 mg/dL.. The lowest value during fasting was 49. Which could be the reason? The body was used to be without food and then  glucose raise when starting to eating again?

It was an interesting experience, but for me it is possible only without working and with a calm familiar settings. If I would do again I would start the refeeding more slowly and with one or two days of only cooked vegetables.


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Hello Sthira, last august I did a 5 days water fasting. I was at my home, no working, I did some taiji and meditation and walking and no other activities. I felt especially weak on the second and third day. In the last two days I had as side effect hiccups. I lost about 1 kg every day.

The day after refeeding my fasting glucose before breakfast arrived at 105 mg/dL.. The lowest value during fasting was 49. Which could be the reason? The body was used to be without food and then glucose raise when starting to eating again?

It was an interesting experience, but for me it is possible only without working and with a calm familiar settings. If I would do again I would start the refeeding more slowly and with one or two days of only cooked vegetables.


I felt really weak and awful on days two and three, too. Dizzy, cranky, weak, bored, questioning why, doubtful, feeling reckless. Emotional and physical discomforts were harsh. Also days five and six sucked pretty sour.


But I'm doing great now -- end of day 11 -- and this is shaping out to be my best, easiest extended fast so far. I've loads of fasting experience, and on this fast a funny thing happened. I broke it after day six, drank pedialyte, ate a small meal then resumed the fast the following day. I'm still fasting now; getting out and about, upending my urban routine -- moving my body in the beautiful, blooming spring nature, doing random handstands, headstands, some slack-lining with friends, generally grooving outside, and not sitting around dying in meditation really helps. My body craves motion. I'm not hungry, a little weak -- I'm about a 60% me, I suppose, and feeling animal pure.


I can't say much of anything about your rise in glucose upon breaking your fast, Cloud -- I guess it would depend upon your personal circumstances, like what you ate and who you are, your general health condition. I'm no fasting expert -- just having fun experimenting with my body -- and I'm digging the challenge.


I am taking vitamins -- B12, D, zinc, magnesium, potassium... So my ongoing fast isn't by any means a pure water-only fast, I'm drinking coffee, too, water, coffee, some vitamins. Pure sunshine, trees, air, watching birds, and not trying to think too much about world-shit.


I have no health problems (beyond depression and general anxiety) and I'm feeling pretty okay about this fast. Maybe even I'm doing my body some good, or at least not harming myself. My sense of smell is wicked strong, my breath rises and falls and tastes like horrible fermented fruit (this is the worst part of this fast -- deeply-rooted rotten fruit breath). My mind is sharp and alert, my body is strong, awake, alive, flexible, open to whatever. This may change suddenly, obviously.


I'm sharing that I have no idea how long I'll keep fasting. If something scary happens -- I faint or get manic, then I'll stop. I'll ramp down with grapefruit, apples, oranges, and stick to fruit, I think, more pedialyte maybe.


Valter Longo's recent cancer-fasting papers had an effect on me. I'm figuring that if it takes mice two or three days to get immunity boosting results, then it'll take us big nasty world-chomping apes much longer to get results (i.e., if we get results at all from extended fasts...)

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I am taking vitamins -- B12, D, zinc, magnesium, potassium... So my ongoing fast isn't by any means a pure water-only fast, I'm drinking coffee, too, water, coffee, some vitamins. Pure sunshine, trees, air, watching birds, and not trying to think too much about world-shit.




Thank you for your report. also mine wasn't a pure water only fast, actually I drank green tea, herbal tea and took some magnesium and salt.

But I could not do much other reading, walking and meditating. My wife and kids have been very understanding. 

Could you do your job during fasting?

I also was very impressed by the recent papers of Valter Longo, even if he told somewhere that he made only one time a water fasting of 5 days and for him was a very difficult experience, therefore he developed the FMD  diet. :)

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I broke my fast today after 12 and a half days in kinda fun way I'll share. I hadn't planned on breaking the fast -- wasn't hungry, felt great, a little weak but gen-a-ok -- but I was bouncing along in a rusted pickup truck in a wetland with a biologist I like and she had a red apple. You won't believe me, but promise this story is true -- we saw a blackracer snake in the dust, so we stopped, checked him out, he was cool, just warming his beautiful body in sunshine, and my friend Eve said haha oh my you should totally break your fast right now with me, Eve, this instant with this apple with this snake in this beautiful wetland paradise you should totally eat this apple right now.


Wouldn't you?


So I did, of course, and now I've resumed feeding my long skinny body the food it deserves. Amenhaha.

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Haha, that's right, now we know and now we toil and now we suffer and that's because someone said to someone else hey eat this luscious juicy fruit goodness.


I think the tricky part of extended fasting is the refeeding. How not to gorge? One method is to just eliminate availability of food. I'm traveling, and I've got a few bags of grapefruit, oranges, apples, and many different kinds of nuts, seeds. What I'm craving mostly is pumpkin seeds! But still, I'm not too hungry. Gorging feels more like a reflex -- something to do when bored, stressed, excited -- than much of anything to do with energy requirements.


I've lost a lot of weight, but haven't weighed myself. I don't want to lose weight -- just want to be pure.

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Fuck knows I ain't no xtian but this little discussion about fasting is great. I'm not so interested in intermittent fasting because I don't like the jerkiness of it, stop, start, stop, start, eat, don't eat, eat, don't eat, I think my body gets weird on that schedule. But long fasts practiced regularly -- start small, skip a day here, there, move slowly to two days, maybe later three, a year later four or five, maybe one time push limits, another time back off...


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The Serpent AdamEveSerpent.jpg

When the woman saw that the tree was good for food, and pleasant to the eyes, and would make one wise, she took the fruit and ate, and she also gave some to her husband, and he ate.

Of all the animals God created, the serpent was the most tricky and deceitful. He came to Eve and asked, "Really? None of the fruit in the garden? God says you must not eat any of it?" "Of course we can eat it," Eve replied. "It's only the fruit from the tree of the knowledge of good and evil that we cannot eat. God says we mustn't eat it or even touch it, or we will die."

"That's a lie!" said the serpent. "You won't die! God knows very well that when you eat it you will become like Him - you will know good from evil!" Eve looked at the fruit on the tree of the knowledge of good and evil and saw that it looked fresh and delicious. She thought the fruit would make her wise like the serpent said it would. Eve was convinced! She picked the fruit and ate it, and she gave some to Adam to eat, too.

The fruit did not make Adam and Eve very wise, but they did realize for the first time that they were not wearing any clothes! They were embarrassed and made themselves skirts of fig leaves.

God Was Angry
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yes well we made for ourselves palmetto fronds, but they're scratchy she said, itchy, and so the bible The Bible is so correct here and we did maybe lose and lose again and maybe she lost more than I lost because (I ate) of the red apple and she saw that it was good and she saw that it was a sun warming blackracer building heat and -- we -- but I wasn't embarrassed and she, but she speaks for herself, so, then ended my fast amen

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I'm figuring that if it takes mice two or three days to get immunity boosting results, then it'll take us big nasty world-chomping apes much longer to get results (i.e., if we get results at all from extended fasts...)



Not really, human studies show that a 3 day water only fast is all it takes (one example of popular press coverage below):



Fasting is great for overweight people or someone that needs to rebuild or prepare their immune system for something (cancer patients), but if you have little or no fat to burn during the fast it can be counterproductive and ravage your muscle, therefore I'm not convinced that extended fasts (especially >3 days) are a good idea for lower BMI individuals.  Muscle is more important than many CRONies seem to give credit to, and plays a role in longevity (and is also related to brown fat activation which may be important for longevity as well).  


The longest water only fast I have done is 3 days, and it was a VERY positive experience, but I only did that once when I was a higher BMI, and I haven't felt the desire or need to do it again since.  I do daily intermittent fasting as well which has been pretty well established in human studies as beneficial, but for me that just means doing all eating during the same 6 hour window every day. 


There's another guy with a great last name, "Ray Cronise" (CRON & ICE the perfect longevity combination, haha)  that you might be interested in, google his name along with fasting and cold.  He has done very long (month?) fasts along with cold exposure.  But his starting point was from a very high (obese) BMI.

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Ray Cronise had an excellent appearance on the Rich Roll Podcast recently. 




You can find it here.  It's a 3hr-ish conversation that most people here would appreciate. 


Yes, I've listened to that interview, it was a very thought provoking and stimulating conversation.

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Ray Cronise had an excellent appearance on the Rich Roll Podcast recently.




You can find it here. It's a 3hr-ish conversation that most people here would appreciate.

Thank you for this great listen. I like his message all the way through from top to bottom. "What is socially extreme," he says, "like fasting water only for 24-days, is not biologically extreme."


Do you agree with this notion? Seems mostly on point in my case: body during my 12.5 day fast was fine (yes some dizziness, some weakness, yeaaaahhhh some feelings of downbeat) but the primary pressures were social. At times I feel so much energy it's amazing -- and I feel, say to myself, observe -- "ok now I'm becoming a bit manic, calm down, relax, control the energy..." And I'm not even very socially wired.


Also I like his idea of having an extended "research vacation" where like-minds gather under supervising researchers and together many of us interested in health and longevity hang out ashram or commune style in some pretty setting. Researchers gather blood samples, bio markers as we each pursue our own chosen paths. I'd pay to do that, I'd leave off work for several weeks for that, I'd put life on hold for that...


Cronice's message inspires me to continue pursuing extended fasts as a promoter of longevity -- and inspiration is very hard to find. I wish we could unite -- but I suppose unification of longevity self-experimentation behaviors is one of the aims of this forum.

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So my ramp-down from the fast hasn't been the smoothest. I'm not really hungry -- yet eating anyway. I don't know about you, but I generally try to eat only when hungry or sliding into weakness. Since breaking my fast -- fruit, nuts, greens, and now I'm back to normal vegan ad lib -- I've found my metabolism has slowed and I really just don't need much to eat. So I'm tempted to start fasting again, but then I think maybe I'll develop an eating disorder this way, so I'm kinda forcing myself to eat.


The fast itself was terrific; the breaking of this fast was less than terrific. But I don't seem to have lost much energy or muscle tone, so that's good, I suppose.


I find myself wanting to resume fasting, but maybe I'll hold off for a month or two. Fasting is really addictive, I think, because it gives me a sense of purpose and a little goal to acheive.

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Thanks for sharing all your fasting experiences. My two cents - don't stop eating again anytime soon. Occasional prolonged fasts can be health-promoting and psychologically quite beneficial. But they take a toll on the body as well, especially for someone without much meat on their bones.


You need time to recover before dipping into the wonderful world of the fasted state again.



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Thanks, Dean, I'll heed your sage counsel, and maybe chop and eat some sage, too. I'm sure you've more common sense than I do, as I tend to push out into extremes, but you do, too... So there's that. I do feel heavy and stuffed even after eating small amounts. But I've mostly been taking it easy, not too much crazy motion and contortionism recently. Feeling heavy and not light after meals is strange.

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  • 3 weeks later...



Here is an interesting story that covers Longo and his approach to Intermittent fasting. It features profiles on folks from Ecuador who have Larson's Syndrome, a genetic condition resulting very low IGF-1 levels. Larson's sufferers are very short but often obese. But they almost never develop either cancer or diabetes.


These health benefits are one of the primary sources of evidence that low IGF-1 (via CR, fasting or pharmacology) might be beneficial in humans, like in animals. Unfortunately, people with Larson's Syndrome don't actually live longer than normal, they just die of other causes.


Anyway, it's an interesting read.



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Now imagine a ten-year old Laron syndrome person who also has (or is modified to express) one of the, um, suspected longevity genes (say, the G allele of the FOXO3 single nucleotide polymorphism rs2802292). And give that lucky little shit a healthy lifestyle (no smoking, kid, remember it's forks over knives, skateboarding prohibited on freeway overpass) water hir seed with great education (Go Golden Bears!) Meanwhile we all experience SENS' slow blooming, what is Calico, we wonder, and eventually -- ta-da! -- there's one fragile flower of potential escape velocity. Hir height is 3' 9" but what is CRISPR-Cas9?


Dean, have you considered adopting?

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Thanks Sthira!


Very amusing and thought provoking, as always.


Dean, have you considered adopting? 


No, my wife and I are done with kids...


... water hir seed with great education ...


Funny you should mention education. I'm in the midst of composing a post to the cold exposure thread about a study demonstrating the importance of cognitive stimulation (in combination with cold & physical exercise) for promoting health and longevity by shrinking and "browning" visceral fat. Here is the introductory post which sets the stage for that one. Stay tuned...



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One of the after-effects of my latest fast has been an uncomfortably strong sense of smell. I'm not exaggerating -- I live in the city and for some reason, although I've fasted a lot in the past, the smells here are overwhelming. I love this little independent coffee joint near my place, but it smells so strongly of chlorine that I'm now avoiding the place. It's unpleasant how many weird chemicals are used to overpower the odors of human urine, which I can smell beneath anyway, I'd actually prefer the odor of urine to what's used to attempt to cover it. This is new for me.


Also I seemed to have lost some of my love for fruit, oddly enough, strange for me because I was an enthusiastic raw fruitarian for awhile. Even berries are too sweet. I couldn't finish a mango. So I've been eating way more leafy greens -- watercress, collards, kale, spinach, chard, but mustard greens are a little harsh now.


My teeth became very white as if I'd had them fakely disguised white although I didn't change my dental habits. If anything, I brushed and flossed less often during the fast.


And I'm really not too hungry much of the time but eating anyway just because BMI is right at 18 and I'm kinda hollowed out and ugly. And my eyelashes got longer (?)...

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The below study seems to confirm the low cancer connection of the Larons, but not other things such as diabetes.  It seems that those from the South American cohort have a separate genetic trait protecting from diabetes in these Larons and others in the general population having the trait.



Laron Z.
Endocr Pract. 2015 Dec;21(12):1395-402. doi: 10.4158/EP15939.RA. Epub 2015 Sep 24.
PMID: 26401581
To describe the characteristics of untreated and recombinant insulin-like growth factor 1 (IGF-1)- treated patients with the Laron syndrome (LS) as seen in our clinic over a period of over 50 years. In 1966, we reported a new disease, characterized by dwarfism (-4 to -10 height standard deviation score) typical facial features, small head circumference, obesity, and small genitalia. They resembled congenital growth hormone (GH) deficiency but had high levels of serum human GH and low IGF-1. Since then, our cohort grew to 69 patients, consisting of Jews of oriental origin, Muslins, and Christians originating from the Middle East or Mediterranean area. Many belong to consanguineous families.
Molecular genetic investigations revealed that these patients had deletions or mutations in the GH receptor gene, but only individuals homozygous for this defect express the disease, coined "Laron syndrome" (LS; Online Mendelian Inheritance in Man# 262500).
During childhood, LS patients grow slowly, have a retarded bone age and sexual development, but reach full sexual development. The treatment of LS is recombinant IGF-1, which stimulates the linear growth but increases the degree of obesity. Adult-age patients with congenital IGF-1 deficiency are protected from cancer but can develop insulin resistance, glucose intolerance, diabetes, and cardiovascular disease. Due to pathologic changes in the brain related to the type of molecular defect in the GH receptor, they vary in their intellectual capacity. A number of LS patients marry, and with help of pregestational genetic diagnosis, have healthy children.
LS is a unique disease model presenting a dissociation between GH and IGF-1 activity.
GH = growth hormone hGH = human growth hormone IGF-1 = insulin-like growth factor 1 LS = Laron syndrome rIGF-1 = recombinant IGF-1 SDS = standard deviation score.
In 1966 (1) and in 1968 (2), we described a disease characterized by severe growth retardation, obesity, and small genitalia, resembling congenital growth hormone (GH) deficiency (3) but with high serum GH levels and low to undetectable serum insulin-like growth factor 1 (IGF- 1). This disease was subsequently coined Laron dwarfism (4) and changed later to Laron syndrome (LS; Online Mendelian Inheritance in Man# 262500). The negative feedback between low IGF-1 and the hypothalamic growth hormone (growth hormone–releasing hormone) leads to an increased secretion of pituitary GH (5). Administration of exogenous human GH (hGH) for 4 to 7 days was shown not to lead to increased serum IGF-1 levels, indicating GH insensitivity as a classic test for this disease (6).
Performing liver biopsies on 2 LS patients in 1983, we found that radioactive iodine–labeled hGH did not bind to liver cell membranes, proving that the mechanism of GH insensitivity of these patients is due to an inability of the GH to bind to its receptors (7). Cloning of the GH receptor in 1987 (8) permitted the study of the molecular defects of this receptor, disclosing the etiopathogenesis of LS. Godowski et al (9), investigating 2 of our patients, found deletions in exons 3, 5, and 6 in the extracellular domain of the GH receptor gene; and Amselem et al (10), using the new method of polymerase chain reaction, described mutations in the GH receptor in Muslim patients from North Africa. Our publications were followed by reports from other parts of the world (11–13). We reviewed our cohort in 2004 (14) and more extensively in 2011 (15).
The aim of this article is to describe the main clinical and biochemical characteristics of LS and to review the lessons we have learned by following and treating a cohort of 69 patients with LS for 50 years. Many of these patients have been followed since infancy into adult age (Table 1). Only when indicated, the findings in our patients are compared with those reported by others.
Table 1
Laron Syndrome – The Israeli Cohort – Age Distribution
During childhood, LS patients grow slowly, have a retarded bone age and sexual development, but reach full sexual development. The treatment of LS is recombinant IGF-1, which stimulates the linear growth but increases the degree of obesity. Adult-age patients with congenital IGF-1 deficiency are protected from cancer but can develop insulin resistance, glucose intolerance, diabetes, and cardiovascular disease.
Demography and Ethnic Origin
It is estimated that there are at least 500 patients with LS worldwide, a number of them still undiagnosed. The great majority of patients originate from the Middle East, Mid and South Asia, and the Mediterranean areas including their descendants. A number of them live now in South and Central America, belonging to consanguineous families (14,16). The largest cohort of almost 100 patients resides in Ecuador (17).
Genetic Aspects
LS is a hereditary disease with a recessive mode of inheritance (18,19). A small number of patients with “de novo” mutations have also been reported (20,21). Only subjects homozygous for the molecular defects of the GH receptor have the disease. First-degree family members, heterozygous carriers of LS, may show certain clinical signs, such as height below the normal mean. At present, 60 mutations of the GH receptor have been reported. The majority are in the extracellular domain of the receptor, and only a few are in the transmembrane or intracellular domains (19,22). Of interest is that almost all patients in South America, including the large cohort in Ecuador, have the same E180 splice mutation (23), the same mutation we found in one of our patients in a Jewish family from North Africa (19). This led to the hypothesis that the LS patients in South America are descendants of Jews who fled the inquisition in Spain in the 15th century and converted to Christianity (called “conversos”) (24).
Clinical Characteristics of Patients With LS
The main clinical features resemble those of congenital isolated GH deficiency (3). As young children, they have a special facial phenotype: small face and chin, protruding forehead, sparse hair, with below-normal head circumference (25–27) (Fig. 1).
Fig. 1.
Typical lateral view of a 1-year-old boy with Laron syndrome. Note: protruding forehead, small face, saddle nose, sparse hair.
Intra-uterine (Prenatal) Period
Contrary to statements that birth length of newborns with LS is normal (28), we found in our cohort that 28 newborns (14 males and 14 females) were below 48 cm (range, 42 to 47 cm), data on 2 babies having been added recently to that previously published (29) (Fig. 2). These findings are in accordance with measurements of newborns with IGF-1 gene deletions (30) and IGF-1 receptor mutations (31).
Fig. 2.
Birth length and weight of neonates with Laron syndrome (LS). The higher weight for length denotes obesity.
Postnatal Linear Growth
Postnatally, growth velocity slows progressively, and the mean height deficit ranges between −4 to −10 standard deviation scores (SDS) below the median of normal height. Untreated male patients reach a final height of 116 to 142 cm, and females reach a height of 108 to 136 cm. Special growth charts for LS have been constructed from the longitudinal follow-up of untreated patients in our cohort (32). It is of interest that children with congenital hGH deficiency are less growth retarded (−3.3 ± 1 SDS height) than children with LS (33). Patients with LS have an upper to lower segment ratio above normal for sex and age, denoting short limbs for the trunk size (34).
The head circumference, denoting brain size, is small (35), similar to that reported for IGF-1 gene deletion (30) and IGF-1 receptor mutations (31).
Extremities and Organ Growth
The hands (36) and feet (37) are small, and so are the internal organs, causing acro- and organomicria (38).
Sexual Development
In childhood, the genitalia are small (39,40) and puberty is delayed, mainly in the males (41), but all reach full sexual development with a normal reproduction potential (42).
The Adipose Tissue
Obesity observed already at birth progresses gradually to excessive measures in adult age, when total body fat reaches between 50 and 60% of body weight in females and 31 to 45% in males (43) (Fig. 3). Determination of nutritional intake and measurement of resting energy expenditure by indirect calorimetry proved that the obesity is not due to an increased caloric intake or reduced energy expenditure (44). Some patients with LS develop nonalcoholic fatty liver disease (45).
Fig. 3.
Obesity in a 19-year-old insulin-like growth factor-1–treated woman with Laron syndrome.
We assume that the GH/IGF-1 deficiency in LS causes an abnormal metabolism in the adipose tissue of LS patients, as evident by the high serum adiponectin levels compared to subjects with the same degree of simple obesity (46). It was disappointing to find that replacement treatment with recombinant IGF-1 (rIGF-1) causes a further increase in the degree of obesity (47). The obesity is accompanied by a progressive increase in serum cholesterol starting in childhood, eventually necessitating treatment with a statin (48).
Carbohydrate Metabolism
Untreated patients with LS have symptomatic and asymptomatic hypoglycemia (49,50). IGF-1 treatment by stimulating somatostatin secretion and insulin suppression (51,52) increases glucose levels and glycated hemoglobin (49). The progressive obesity leads to insulin resistance, which causes in some patients glucose intolerance, even in adolescence (53), and diabetes in adults. If not properly controlled, the diabetes causes vascular complications (54). In our adult cohort, we have registered 16 patients with glucose intolerance and 7 patients with type 2 diabetes. Six of these patients with type 2 diabetes are men and 1 is a woman, and the age at conversion from subclinical to clinical diabetes ranged between 37 and 60 years (16).
Diabetes has also been reported in an LS patient from Turkey (55) and in patients with congenital hGH gene deletions (56). These results differ from those reported in the Ecuadorian cohort (57). The explanation may be that patients with the E180 splice mutation, common to all Ecuadorian patients, differs in the risk for diabetes from other mutations. Our patient with this mutation, age 36 years, had a normal glucose tolerance test at her last examination.
Muscle Mass and Force
Patients with LS have a reduced lean body mass (44) and reduced muscle force and endurance (58).
Skeletal System
Using dual-energy X-ray absorptiometry, LS patients have been found to have a reduced bone mineral density; however, recalculation of the volumetric density (bone mineral areal density) revealed normal values (59). Different modalities of X-rays and computed tomography revealed a series of pathologies, such as marked retardation of bone age, thin bones, a small base of the skull, small facial bones (25) (Fig. 4), thin calvaria, underdeveloped frontal and paranasal sinuses (60), frequent anomalies of the os odontoideum, and spinal stenosis of the cervical and lumbar spine (61).
Fig. 4.
Anterior-posterior X-ray of a 9-year-old girl with Laron syndrome. Note: disproportion of the width of the calvaria compared to that of the base of the skull. The sagittal suture is still open, denoting bone-age retardation.
Brain and Oropharynx
Using magnetic resonance imaging, a series of pathologies in the brain were found in some patients. We observed various degrees of diffuse parenchymal loss, small cerebellum with enlarged folia, and fissures compatible with cerebellar atrophy, as well as mild ventricular enlargement (60,62). These pathologies may not be specific, as they are found in numerous metabolic or infections disorders (63). These changes, together with the microcrania in LS, denoting underdevelopment of the brain, seem to contribute to the wide spectrum of intellectual abilities of these patients.
Intellectual Functions
Probably due to a combination of delayed and slow brain growth (64) and variable abnormalities in the brain, patients with LS present with a wide range of psychological deficiencies, as found by repeated testing, and which span from normal intelligence quotient (IQ) to mental retardation (64,65). Some of the variations in IQ are explained by the different GH receptor defects, such as in patients with the E180 splicing mutation, who seem of normal intelligence (66), and those with exons 3, 5, and 6 deletions of the GH receptor have the most serious mental defects (67).
Other Handicaps
Major handicaps in the untreated patients are short stature and progressive obesity, resulting in orthopedic problems, hyperlipidemia, cardiovascular disease, glucose intolerance, and diabetes. The spinal stenosis found in a number of patients leads to peripheral neurologic disorders. LS patients also have various degrees of auditory defects (68). Unfortunately, most handicaps are not ameliorated by IGF-1 treatment.
Social Problems
Depending on the society and culture in which LS patients live, the social problems in childhood and adult age can be minimal to severe. They start in school, occupation, and raising a family. Short stature itself is not a hindrance to social adjustment and quality of life (Fig. 5). Of the 48 adult patients in our LS patient cohort, 10 (5 men and 5 women) are married with children, and all but 2 of the patients have reported sexual relations.
Fig. 5.
The manner in which human growth hormone (hGH)/insulin-like growth factor-1 (IGF-1) deficits affect social adjustment and quality of life.
Longevity and Mortality
As shown in Table 1, 21 patients (8 men and 13 women) are over age 50 years; our oldest patient, aged 78 years, died in an automobile accident. In our cohort, we registered 5 deaths; 1 patient, aged 4 years, died of suspected encephalitis before referral; 2 died due to coronary heart disease; 1 died under anesthesia for the treatment of status epilepticus; and 1 died in an automobile accident.
Advantages: Protection from Cancer
Considering the role of the GH–IGF-1 axis on normal and pathologic growth, we studied the prevalence of malignancies in our cohort of LS patients and in a worldwide enquiry comprising 230 LS patients. We found that LS patients homozygous for the GH receptor defect causing GH inactivity and congenital IGF-1 deficiency are protected from developing cancer, even after long-term IGF-1 treatment. Their heterozygote relatives are not protected (69,70). Our findings were confirmed in the Ecuadorian cohort of over 90 patients (57). Research on the mechanism of cancer protection showed an increase in the expression of cancer-protective genes and a decrease in the expression of cancer-stimulating genes (71).
The only treatment of LS is daily IGF-1 administration (72). After having studied the pharmacology of recombinant IGF-1, we treated 21 children (10 boys and 11 girls) with rIGF-1 until the achievement of adult height (73). IGF-1 stimulated linear growth, acral, and organ growth (36,37,73) but increased the adipose tissue mass (47). Mean growth velocity in the first year of treatment was 8 cm/year. Linear growth catch-up and changes in the upper to lower body ratio showed a change in height SDS from −6.1 ± 1.3 to −4.6 ± 1.2 SDS (P<.001), without change in the upper to lower body ratio. IGF-1 increased the mean (±SD) head circumference from −3.3 ± 0.9 to +0.87 ± 1.8). Short-term treatment of adults with LS reduced body lipids slightly (52) (no long-term treatment for adult patients with the aim of strengthening the muscular and skeletal systems has been approved as yet). A single injection of rIGF-1 (150 to 220 μg/kg in children) resulted in the same growth-promoting effects as 2 daily injections and caused fewer adverse effects (72,73,74). rIGF-1 treatment increased androgen secretion and stimulated penile growth (75), but less so testicular growth. rIGF-1 treatment also caused a significant increase in the red blood indices, with an increase in blood hemoglobin (76). Unfortunately, the majority of children with LS worldwide are not treated due to a lack of national insurance programs for “orphan diseases” (16).
Followed over 50 years, the large Israeli cohort of LS patients permitted the study of the sequelae of concomitant congenital deficiency of both these hormones as well as the responses to treatment with IGF-1, in the absence of hGH activity.
Children with a congenital deficiency of both GH and IGF-1 activity are shorter than children with congenital isolated GH deficiency alone.
Obesity in LS children starts in utero and increases postnatally in a progressive manner, and their abnormally high serum adiponectin denotes a pathologic process in the adipose tissue.
IGF-1 treatment stimulates linear growth, but less than hGH in isolated GH-deficient children.
One daily injection of IGF-1 has the same effect as 2 daily injections, with fewer adverse effects.
No treatment has been found so far for the obesity associated with LS, which progresses during IGF-1 treatment.
Diagnosis and treatment of LS is important, as the developing obesity, hyperlipidemia, and glucose intolerance progress with age and lead to cardiovascular disease and diabetes.
Patients with LS are protected from developing cancer, even when treated with rIGF-1.
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