Endocrine Diseases

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' Basics, Hypothalamus, Pituitary gland'''

Hormones are responsible for homeostasis of internal milieu of organism, regulation of metabolism, adaptation to stress. Their deficiency causes endocrine diseases. Hormones are produced in endocrine glands but also by specialized cells in brain, kidneys, gastrointestinal tract, lungs, etc.

Deficiency of hormones was historically the first indication for fetal cell transplantation. The same is not true with the excessive production of hormones: hyperfunction of any endocrine gland is an indication for fetal cell transplantation only in the case that an antagonist of the hormone is known, and is produced by a specific cell type, that is then used for cell transplantation treatment. Although several antagonists of thyroid hormones are known, as well as cell types producing them, they affect Graves, or Basedow, disease only to a limited degree. The same applies to Cushing’s syndrome.

Because of complex interrelationships of endocrine glands, and their control by hypothalamus/pituitary gland, it is very rare that a specific patient gets cell transplantation of a single type of cell only rather than cell transplants of all related glands, and of hypothalamus and pituitary are implanted, too.

From chemical viewpoint hormones can be

1/ polypeptides and proteins, produced on ribosomes, as pre-prohormones first: after removal of a ‘signal peptide’ a pro-hormone is created, which then, after the next biochemical step, becomes a hormone;

2/ steroids;

3/ low-molecular amines (catecholamines, thyroid hormones).

Hormones do not influence cell functions directly, only through secondary intracellular signals. Active hormone is secreted into blood and taken by protein carrier to the target cells of the respective tissue, the first messenger, that accepts from the multiplicity of data only what is pertinent. This selection of data is possible via specific receptors on the cell surface, macromolecules with a high affinity for the given hormone and capability to communicate with the hormone. Connection of hormone with its specific receptor creates ‘hormonal system’, that enables entry of the hormone into the cell, i.e. internalization. Thereby a cascade of secondary effects is triggered, including the creation of intracellular ‘second messengers’:

- activation of membrane adenylatecyclase by the complex ‘hormone-receptor’,

- creation of cyclic AMP from ATP by adenylatecyclase,

- activation of proteinkinases (phosphokinases), that catalyse phosphorylation of various proteins, mainly enzymes, and thereby activate them as well.

Many peptide hormones utilize cyclic adenosinmonophosphate(cAMP) as a ‘second messenger’, such as ACTH, luteotropin(LH), thyreotropin(TSH), prolactin, somatotropin, portion of releasing hormones(RH) and release inhibiting hormones(RIH), glucagons, parathormone, calcitonin, ADH, gastrin, secretin, oxytocin, adenosine, serotonin, dopamine, histamine, and prostaglandins. Cyclic guanosinmonophosphate (cGMP) is a ‘second messenger’ for atrial natriumuretic factor, and nitrogen oxide(NO). The same hormone may, depending upon the target cell and receptor, cause production of various ‘second messengers’.

The remaining molecular mechanisms take place in the cell nucleus, that secures and regulates the expression of respective target genes. This is carried out via third messengers, or ‘transcription factors’, the proteins bound to the specific DNA sequences in the regulatory portion of these genes, and causing stimulation or suppression of the gene expression. The result is the realization of respective metabolic response, specific for the effect of the hormone in the respective target organ.

Hormones regulate and direct function of organs. Stimulation (or inhibition) of their release is controlled by specific factors. Hormones act upon the hormone producing cell itself via autocrine effect, or upon the neighboring cells via paracrine effect through mediators or neurotransmitters, or upon distant target cells in other organs via endocrine effect. Hormones must not be inactivated before reaching their target cells. In target cells hormones are bound to receptors and trigger intracellular signal transduction to accomplish their effect.

Some hormones must be converted to the active form at the periphery. If such conversion is not possible, because of enzymatic defect, the hormone remains inactive. Finally, hormone can be inactive due to the lack of sensitivity of target organs, i.e. there is a defective hormone receptor, or intracellular transport, or complete malfunctioning of target cells or organs.

The cause of increased hormonal effect can be an abnormally high level of release of hormone cellular transport, or hyperfunction of hormone sensitive cells.

Hormones are usually components of regulatory circuits. Disturbance of one unit of regulatory circuit leads to characteristic changes of other units of the circuit.

In endocrine system a regulatory circuit with negative feedback dominates since the production of a hormone of the target endocrine gland in the periphery usually lowers a release of the hormone from the regulatory gland via reduction of stimulatory factors.

Regulatory circuits with positive feedback, i.e. when hormones of the target endocrine gland in the periphery lead to increase of stimuli, and thereby support of their own release, are rare and usually only temporary.

Release of hormones is directed by hypothalamus and pituitary: ‘Releasing hormones’ are produced in hypothalamus and cause the release of respective tropins in pituitary. In turn, tropins stimulate the release of the respective hormone at the periphery. The hormone at the periphery, and to some degree also its effects, suppress the release of releasing hormones in hypothalamus and of tropins in the pituitary. Decreased release of the peripheral hormone can be due to the disturbance of the function of hypothalamus, pituitary or the peripheral endocrine gland.

A comment about a disease frequently encountered in the medical practice of cell transplantologists called ‘stress syndrome’ or ‘manager’s disease’. If you can handle such patients, usually non-compliant, then fetal precursor cell transplantation of diencephalon, thalamus, hypothalamus, frontal lobe of brain, adrenal cortex, gonads, is recommended.

Fetal precursor cell transplantation takes vastly different approach to the treatment of endocrine diseases as compared with the use of individual hormones:

1/ hormones are produced, and released by organism as necessary, there is no storage of active hormones;

2/ hormones have only short-term effect, while transplanted cells long-term therapeutic benefit;

3/ hormone replacement therapy is a treatment for life, without possibility of cure;

4/ long-term hormone replacement therapy suppresses the respective endocrine gland, and cause atrophy and loss of function of the gland.

Hypothalamus, Pituitary'

Somatotropin, growth hormone, is produced in anterior lobe of pituitary. It inhibits intake of glucose into muscle and fatty cells, supports lipolysis, gluconeogenesis, collagen synthesis, erythropoietin synthesis. It also stimulates resorption of calcium and phosphorus in the intestine, as well as excretion of calcium through kidneys. It supports bone growth before closure of epiphyses, and thereby also height, and growth of soft tissues, and stimulates proliferation of T-cells, IL-2, ‘killer’ cells, macrophages, and thereby the entire immune system.

The release of somatotropin is stimulated by growth hormone releasing factor, and inhibited by somatostatin, from hypothalamus.

Excess of somatotropin is usually due to pituitary adenoma, and causes acromegaly.

Insufficient release of somatotropin before the closure of epiphyseal ossification centers leads to pituitary nanismus, while later on in life it cannot be easily detected but has to be watched for in case of immune system weakness in elderly.

Various forms of endocrine nanismus are disorders of the axis hypothalamus - anterior lobe of pituitary – adrenal cortex – gonads.

Nanismus, or dwarfism, was historically one of the first indications for fetal cell transplantation. In the first two years of life cell transplants necessary for treatment are selected according to the etiology summarized below. Between 3rd and 8th year of life diencephalon, hypothalamus, anterior lobe of pituitary, thyroid, has to be implanted as well, and after 8th year of life adrenal cortex and gonads.

Pituitary nanism due to the isolated deficit of growth hormone, or somatotropin, an AR disorder, (but can be also AD or XR), is a ‘nearly’ proportional nanism with normal sexual development, with delayed development of facial skeleton, delayed permanent dentition, progeric facies, typical voice, hair and nail abnormalities, hypoglycemia, etc. It can be due to any mis-step along the pathway from the release of neurotransmitters by neurons of brain cortex and suprahypothalamic region, that stimulate the release of growth hormone releasing factor (GHRF), or somatoliberine, from hypothalamus, and that in turn stimulates respective cells of anterior lobe of pituitary to secrete the growth hormone. Finally, growth hormone stimulates the receptors of multiple tissues, mostly liver, where Insuline-like Growth Factors IGF-I (somatomedin C) and IGF-II (somatomedin A) mediate the activity of growth hormone. Testing permits today to differentiate the cause of nanism as being of pituitary or of receptor origin.

Laron nanism is an AR disorder occuring in Jews, with accentuated nanism, abnormal facial expression, high-pitch voice, small external genitalia, but normal reproductive ability, acromicria, and trunk obesity, delayed dentition, and closure of major fontanelle. Failure of response of membrane receptors to the growth hormone is the cause. [233]

Other forms of nanism, and its etiology, are

-proportionate: - hereditary, e.g. familial, constitutional, progeria, pseudo-hypo-parathyreoidism,

- metabolic: renal, i.e. Debre-de Toni-Fanconi syndrome, phosphate diabetes, vitamin-D-resistant rachitis, or intestinal, i.e. megacolon, pancreatic fibrosis, orhepatic, i.e. glycogenoses, mucopolysaccharidoses, cystinosis, lysosomal storage disease.

- nearly proportionate:

- neuro-endocrine, i.e. hypothyreosis, adrenal, dysgenital, or dyscerebral, e.g.Down syndrome, microcephaly, Laurence-Moon-Biedl syndrome, - hypoxemic, i.e. cardiac, pulmonary, anemic,

- disproportionate: - defective bone growth: chondrodystrophy, achondroplasia, osteogenesis imperfecta, chondroectodermal dysplasia, Morquio disease, Hurler disease, Sanfilippo disease, marble bone disease, dysostosis cleidocranialis.

Our own experience in the treatment of familial and constitutional nanismus, without any deficit of growth hormone, by human fetal cell transplantation in 11 patients at the Endocrinology Research Center of the Russian Academy of Medical Sciences was positive. Our patients were from 4 to 15 years of age, 7 males, 4 females. With the exception of slightly higher TSH in 2 patients, the hormonal testing was normal in all patients. Fetal cell transplantation of hypothalamus, entire pituitary, thyroid, was carried out for patients up until 8 years of age, and after that age also cell transplants of gonads and adrenal cortex was implanted. Four patients received also the 2nd cell transplantation. Within 3 months of cell transplantation the height of all patients increased by 2.0 to 2.5. cm, but the response was not as pronounced as typically seen in the proportionate nanismus due to growth hormone deficiency.

Diencephalon/hypothalamus system is involved in many disturbances of growth, weight loss, obesity, and so fetal precursor cell transplantation of such cells should be considered in various affections of brain. [271, 272, 273]

One of those is post-partum Sheehan syndrome, that often appears silently, and leads to a variety of ‘hormone’ problems without any effective treatment. Fetal precursor cell transplantation of diencephalon, adrenal cortex, ovary, placenta, liver, intestine, is recommended.

Another is anorexia neurosa’, or ‘bulimia’, where fetal precursor cell transplants of diencephalon, hypothalamus, anterior lobe of pituitary, adrenal cortex , gonads, should be considered ‘when everything else fails’.

Anorexia nervosa is a very hard to treat condition, so it is of no surprise that fetal cell transplantation was tested as a treatment of such patients. A wife/husband team developed a therapeutic program which includes all steps known and described, but after a proper preparation of patient it is a cell transplantation of thymus, spleen, placenta, ovaries, diencephalon, liver, stomach/intestine, exocrine pancreas, thyroid, that makes the difference. The report is based on an experience with the first 10 patients, all of them ‘failures’ of the previous therapeutic attempts, two of them described in detailed case histories.

Overall when compared with published data about 54 patients treated by traditional methods, the 10 reported patients spent 10 days in outpatient preparatory phase, then 5 – 10 days as in-patients, during which time they received fetal cell transplantation, and 32 – 50 days in the follow-up ambulatory care, while those 54 patients spent 32 – 749 days in outpatient preparatory phase, then 6 – 175 days as in-patients, and 28 – 630 days in the follow-up ambulatory care. It seems apparent that fetal cell transplantation makes the difference. [296]

Even the treatment of obesity can be assisted by fetal precursor cell transplantation in motivated patients by implanting diencephalon, hypothalamus, entire pituitary gland including infundibulum. Many young females develop obesity during the first pregnancy, that is not responsive to diet and exercise. Here the regeneration of the entire endocrine system should be carried out by fetal precursor cell transplantation of diencephalon, hypothalamus, entite pituitary including infundibulum, thyroid, adrenal cortex, ovary, placenta .

Antidiuretic hormone, ADH, or vasopressin, is produced in nucleus supraopticus and paraventricularis of hypothalamus and is transported through axons of the hormone producing neurons into the posterior lobe of pituitary. ADH influences channels for H2O in distal tubules and collecting tubules of kidneys and supports water reabsorption. It stimulates also reabsorption of Na+ and urea, and in high concentrations causes vasoconstriction.

Lack of ADH can be genetic, i.e. diabetes insipidus, or due to autoimmune destruction of ADH producing neurons, or any other hypothalamic damage. Fetal precursor cell transplantation of hypothalamus, entire pituitary including infundibulum, kidney, placenta, is advised.

In renal diabetes insipidus there is a defect of channels for water, and thereby of concentration ability of kidneys, as for example with low levels of K+, excess of Ca++, or inflammation of renal medulla.

Our study of treatment of central diabetes insipidus in children by transplantation of human fetal cells of diencephalon, pituitary, kidney, hypothalamus, was carried out at Endocrinology Research Center of Russian Academy of Sciences and included 5 children, of 3 to 15 years of age, 3 females, and 2 males. Three patients suffered also from autonomous nervous system disorder with hypotonia and two female patients from chronic pyelonephritis. Two patients had atopic dermatitis. One female patient, nearly 16 years old, received fetal cell transplantation three times, and her dose of ADH decreased after the 1st cell transplantation from 6 drops to 1 – 2 drops, and has remained the same for over 18 months, her headaches disappeared completely, as well as dysmenorhea. Another female patient, 11 years old had cell transplantation twice, her dose of ADH decreased to 1 – 2 drops a day, thirst and polyuria disappeared, headaches were less frequent. In all three remaining patients the ADH dose was substantially decreased, headaches less pronounced or disappeared.