15.1: Age Related Changes to the Endocrine System - Biology

15.1: Age Related Changes to the Endocrine System - Biology

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The endocrine system arises from all three embryonic germ layers. The endoderm gives rise to the thyroid and parathyroid glands, as well as the pancreas and the thymus.

As the body ages, changes occur that affect the endocrine system, sometimes altering the production, secretion, and catabolism of hormones. For example, the structure of the anterior pituitary gland changes as vascularization decreases and the connective tissue content increases with increasing age. This restructuring affects the gland’s hormone production. For example, the amount of human growth hormone that is produced declines with age, resulting in the reduced muscle mass commonly observed in the elderly.

The adrenal glands also undergo changes as the body ages; as fibrous tissue increases, the production of cortisol and aldosterone decreases. Interestingly, the production and secretion of epinephrine and norepinephrine remain normal throughout the aging process.

A well-known example of the aging process affecting an endocrine gland is menopause and the decline of ovarian function. With increasing age, the ovaries decrease in both size and weight and become progressively less sensitive to gonadotropins. This gradually causes a decrease in estrogen and progesterone levels, leading to menopause and the inability to reproduce. Low levels of estrogens and progesterone are also associated with some disease states, such as osteoporosis, atherosclerosis, and hyperlipidemia, or abnormal blood lipid levels.

Testosterone levels also decline with age, a condition called andropause (or viropause); however, this decline is much less dramatic than the decline of estrogens in women, and much more gradual, rarely affecting sperm production until very old age. Although this means that males maintain their ability to father children for decades longer than females, the quantity, quality, and motility of their sperm is often reduced.

As the body ages, the thyroid gland produces less of the thyroid hormones, causing a gradual decrease in the basal metabolic rate. The lower metabolic rate reduces the production of body heat and increases levels of body fat. Parathyroid hormones, on the other hand, increase with age. This may be because of reduced dietary calcium levels, causing a compensatory increase in parathyroid hormone. However, increased parathyroid hormone levels combined with decreased levels of calcitonin (and estrogens in women) can lead to osteoporosis as PTH stimulates demineralization of bones to increase blood calcium levels. Notice that osteoporosis is common in both elderly males and females.

Increasing age also affects glucose metabolism, as blood glucose levels spike more rapidly and take longer to return to normal in the elderly. In addition, increasing glucose intolerance may occur because of a gradual decline in cellular insulin sensitivity. Almost 27 percent of Americans aged 65 and older have diabetes.

Stress and hormones

In the modern environment one is exposed to various stressful conditions. Stress can lead to changes in the serum level of many hormones including glucocorticoids, catecholamines, growth hormone and prolactin. Some of these changes are necessary for the fight or flight response to protect oneself. Some of these stressful responses can lead to endocrine disorders like Graves’ disease, gonadal dysfunction, psychosexual dwarfism and obesity. Stress can also alter the clinical status of many preexisting endocrine disorders such as precipitation of adrenal crisis and thyroid storm.

15.1: Age Related Changes to the Endocrine System - Biology

Female fertility (the ability to conceive) peaks when women are in their twenties, and is slowly reduced until a women reaches 35 years of age. After that time, fertility declines more rapidly, until it ends completely at the end of menopause. Menopause is the cessation of the menstrual cycle that occurs as a result of the loss of ovarian follicles and the hormones that they produce. A woman is considered to have completed menopause if she has not menstruated in a full year. After that point, she is considered postmenopausal. The average age for this change is consistent worldwide at between 50 and 52 years of age, but it can normally occur in a woman’s forties, or later in her fifties. Poor health, including smoking, can lead to earlier loss of fertility and earlier menopause.

As a woman reaches the age of menopause, depletion of the number of viable follicles in the ovaries due to atresia affects the hormonal regulation of the menstrual cycle. During the years leading up to menopause, there is a decrease in the levels of the hormone inhibin, which normally participates in a negative feedback loop to the pituitary to control the production of FSH. The menopausal decrease in inhibin leads to an increase in FSH. The presence of FSH stimulates more follicles to grow and secrete estrogen. Because small, secondary follicles also respond to increases in FSH levels, larger numbers of follicles are stimulated to grow however, most undergo atresia and die. Eventually, this process leads to the depletion of all follicles in the ovaries, and the production of estrogen falls off dramatically. It is primarily the lack of estrogens that leads to the symptoms of menopause.

The earliest changes occur during the menopausal transition, often referred to as peri-menopause, when a women’s cycle becomes irregular but does not stop entirely. Although the levels of estrogen are still nearly the same as before the transition, the level of progesterone produced by the corpus luteum is reduced. This decline in progesterone can lead to abnormal growth, or hyperplasia, of the endometrium. This condition is a concern because it increases the risk of developing endometrial cancer. Two harmless conditions that can develop during the transition are uterine fibroids, which are benign masses of cells, and irregular bleeding. As estrogen levels change, other symptoms that occur are hot flashes and night sweats, trouble sleeping, vaginal dryness, mood swings, difficulty focusing, and thinning of hair on the head along with the growth of more hair on the face. Depending on the individual, these symptoms can be entirely absent, moderate, or severe.

After menopause, lower amounts of estrogens can lead to other changes. Cardiovascular disease becomes as prevalent in women as in men, possibly because estrogens reduce the amount of cholesterol in the blood vessels. When estrogen is lacking, many women find that they suddenly have problems with high cholesterol and the cardiovascular issues that accompany it. Osteoporosis is another problem because bone density decreases rapidly in the first years after menopause. The reduction in bone density leads to a higher incidence of fractures.

Hormone therapy (HT), which employs medication (synthetic estrogens and progestins) to increase estrogen and progestin levels, can alleviate some of the symptoms of menopause. In 2002, the Women’s Health Initiative began a study to observe women for the long-term outcomes of hormone replacement therapy over 8.5 years. However, the study was prematurely terminated after 5.2 years because of evidence of a higher than normal risk of breast cancer in patients taking estrogen-only HT. The potential positive effects on cardiovascular disease were also not realized in the estrogen-only patients. The results of other hormone replacement studies over the last 50 years, including a 2012 study that followed over 1,000 menopausal women for 10 years, have shown cardiovascular benefits from estrogen and no increased risk for cancer. Some researchers believe that the age group tested in the 2002 trial may have been too old to benefit from the therapy, thus skewing the results. In the meantime, intense debate and study of the benefits and risks of replacement therapy is ongoing. Current guidelines approve HT for the reduction of hot flashes or flushes, but this treatment is generally only considered when women first start showing signs of menopausal changes, is used in the lowest dose possible for the shortest time possible (5 years or less), and it is suggested that women on HT have regular pelvic and breast exams.

Male Reproductive System

As a result of the cumulative changes to the male reproductive system many men experience depression, mood swings, and a general feeling of uneasiness as they approach their 50s or 60s. This time period is referred to as andropause, or male menopause. While the testes continue to function during and after this period men may experience impotence. Regardless, even at advanced ages, some men are able to have sexual relationships and may even remain fertile.

Physiologically the testes decrease in size and firmness with age. This is associated with a gradual age related decline in the secretion of testosterone. Simultaneously there is a decrease in sexual desire. By the age of 60 there is a 30% reduction in sperm count. The prostate gland atrophies between the ages of 50 and 60 years of age, which reduces the secretory capacity. By the age of 70 the prostate gland may enlarge due to masses of potentially cancerous tissue. Additionally the seminal vesicles decrease in weight and storage capacity after age 60 and the penis undergoes some atrophy with age.

Altered immunity in older adults and COVID-19

Biological aging is an inevitable process which causes functional decline in affected cell-tissue-organ-system chain of the living organism. Together with the cellular aging, unfavorable aging-related immune system changes, termed as “immunosenescence” seems to be at the bottom of various age-related chronic diseases and the vulnerability to acute clinical conditions, particularly infections. On the other side, this remodeling occurs due to the struggle of the organism to maintain the homeostasis and adaptation to environmental stressors [13]. It is shaped under interactions of multiple intrinsic factors including genetics, sex hormones, insulin resistance, and adiposity [14] and various acute and chronic extrinsic or intrinsic factors might accelerate or decelerate its progression [15]. Therefore, phenotype and pace of both immunosenescence and cellular senescence progression is not uniform and might differ between individuals regardless of chronologic age. Hence, it would be a rather superficial approach to only focus on the statistics from the clinical data observed in certain age groups by ignoring the heterogeneity of clinical characteristics of the older patients. We believe that this subject should be examined in terms of the aging-related decrease in function at the level of organ, tissue or even cell, which is individualized by the genetic background, neuroendocrine factors which too are subject to alter with aging, and other risk factors for each patient.

Cellular senescence

Cellular senescence describes a state that cell enters due to a current stressful condition and the first identified of these stress situations is telomere shortening [16]. It is characterized with permanent cell cycle arrest, and hypersecretion of various proinflammatory mediators to trigger the immune system to eradicate this stressor [17]. However, the word 'senescence' here may sound misleading as if it refers to diminishing functions of an aging cell near to death. Contrarily, senescent cells are actively secreting and highly viable. In fact, it is not the cellular senescence itself, but the accumulation of chronic senescent cells induced by persistent and cumulative damage, leads to the decrease in tissue function and their secretome contribute to the mild chronic inflammation of aging, referred as ‘inflammaging’ [15]. While the molecules produced by senescent cells, altogether termed as senescence-associated secretory phenotype (SASP), might vary from cell to cell, their common feature is that they are pro-inflammatory in nature [14], and work as an ‘inflammatory-call’ to immune system in case of any stress exposure, including infection. In the aging process, SASP creates its self-feeding cycle by triggering senescence in both normal and progenitor cells of functioning tissues via paracrine activity [15].

Older age, male sex and multimorbidity are the most important risk factors for severe COVID-19 [5]. Even at first glance it seems obvious that these are the very same factors that increase cellular senescence and immunosenescence. Furthermore, there are some more important clues that support this suspicion. Telomere length (TL), particularly that of lymphocytes is known to be a critical marker of biological aging. Such that, lymphocytes with shorter TL are among the drawbacks of aging immune system which significantly contributes vulnerability to certain infections due to their decreased reconstitutive capacity. In line with that, regardless of age, shorter TL has been found to be associated with both severe COVID-19 [18, 19], and its risk factors: increasing age, aging-related diseases, and male sex [20]. The senescence of epithelial and stromal cellular components of the lungs probably facilitates replication of SARS-CoV-2 already, as locally increased interleukin (IL)-6 recruits myeloid-derived suppressor cells and establishes an immunosuppressed microenvironment [21, 22]. The diminished regeneration-competence of senescent type-II alveolar cells and Tɫ lymphocytes with shorter TLs seem to be explanatory to severe-COVID-19-related lung tissue damage and lymphopenia, respectively [18�]. Additionally, certain SASP components like nuclear factor-kappa B (NF-㮫) downstream cytokines and type-I interferons (IFNs) contribute cellular senescence by inducing telomere attrition [23] which in turn sustains this vicious senescence਌ycle. On the other hand, severe COVID-19 is driven by suppressed IFN-I response whose inducibility is already found to be decreased in aging to balance its cellular senescence triggering effect [24]. In other words, the blunted IFN-I response seems to be an adaptive mechanism to keep the pace of the cellular senescence under control in expense of an increased vulnerability to SARS-CoV-2 infection.

Aside from the important influence of well-known factors such as genetics, hormonal changes, and cumulative stress of aging, cellular senescence -regardless of the age- could be accelerated or even initiated by certain aging-related chronic diseases and major stressors including acute diseases like viral infections [15]. According to the current evidence, triggering a senescence chain by either directly infecting cells or indirectly via paracrine effect of the released proinflammatory cytokines seems like an important sword of SARS-CoV-2 [25].

Cytokine storm is the characteristic feature of the clinical deterioration in COVID-19 and it is the uncontrolled production of proinflammatory cytokines whose baseline secretion is already increased in the context of inflammaging [14]. Mitochondrial dysfunction which could briefly be described as disrupted homeostasis of mitochondria in favor of fusion and elongation, and iron dysregulation which further aggravates oxidative stress produced by aging-mitochondria are also among the overlapping mechanisms for cellular senescence and severe COVID-19 [26, 27].


Immunosenescence is the term that describes age-related malfunctioning of both innate and adaptive immunity and dysregulation of their interactions. It is well-known that immunosenescence is mainly responsible from increased vulnerability to severely progressive acute infections like pneumonia or sepsis [28]. Also, we have plenty of knowledge about how each immune cell type is affected in terms of function and proportion, however there are still lots of gaps to fill for thoroughly understanding immunosenescence and the mechanisms that lead to it.

Immunosenescence is characterized by impaired recognition and antigen presentation of pathogens by innate immunity, reduced ability to generate specific immune responses due to polarization of lymphocytes from naïve to memory cells despite increased basal pro-inflammatory tone: inflammaging [29]. Broadly, it is not simply the loss of function of the immune system rather its dysregulated or improper response to infectious agents and autoinflammatory/hyperinflammatory reactions that is prone to failure in terms of clinical outcomes and effectivity of vaccines [28, 30]. Being unable to develop an effective specific response, the main handicap of immunosenescence seems to be impairment in coping with novel pathogens like SARS-CoV-2 [31].

PRRs, IFN-I, antigen presenting cells

Recognition of pathogen and damage associated molecular patterns is the initiating step for the immune response against SARS-CoV-2. As an RNA virus, SARS-CoV-2 is mainly sensed by transmembrane toll-like receptors (TLRs) 3,7,8 and cytosolic RIG-1-like receptor (RLR). Almost all types of pattern recognition receptors (PRRs) were found to be lower in antigen presenting cells (APCs) of older adults [24, 31] and demonstrated lower cytokine production upon stimulation [24, 31, 32] (Fig.  2 ). This impaired effectivity of PRRs blunts the downstream steps to produce type-I IFNs and NF-㮫 centered cytokine response. Type-I IFNs (IFN-α and -β) are the molecules of utmost importance for antiviral response in SARS-CoV-2 [33]. Type-I IFNs generate expression of various IFN-inducible genes which provides the phenotype change of the target cell in a way that prevents viral replication and metabolism, besides trigger T-cell activation for the virus-specific immune response [34]. Based on the knowledge that earlier SARS-CoV infection, the causative agent of SARS, induces downregulation of Type-I IFNs that resulted in an impaired innate immune response [35, 36], a similar strategy was also described for SARS-CoV-2 [33, 37] (Fig.  2 ). Additionally, Hadjadj reported that unlike mild and moderate groups, in severe and critical COVID-19 patients, global IFN-I response was significantly downregulated, which seemed to be climacteric as it preceded clinical deterioration to respiratory failure [38]. Antiviral IFN-α response was already shown to be delayed [32] and the dynamism of the induced IFN responses is impaired with aging independent from PRR signaling [24, 39]. Correspondingly, the course of IFN-α response was low or even absent in critical COVID-19 patients, high but short-lived in severe patients, whereas sustainably powerful in mild and moderate cases [38]. An insufficient initial IFN-I response is critical for later course of infection, as it results in uncontrolled viral replication. The higher viral loads in the plasma samples of severe and critically ill COVID-19 patients [38] and in oropharyngeal saliva samples of older patients [40] are likely to reflect such a lack of control on viral replication. Likewise, higher titers of viral shedding which were significantly more common in males and older patients were related to more rapid course of SARS and higher mortality rates [41]. These results also might be explained with the failure of early innate immune response by IFN-I which is brought by immunosenescence.

Immunosenescence mechanisms paving the way for severe COVID-19. Immunosenescence is the gradual unfavorable alterations in innate and adaptive immune mechanisms with aging. Diminished pathogen recognition, attenuated virus-induced IFN-I respose and dysfunctional macrophages/monocytes are the drawbacks of innate immunity that fail to provide the first line of defense to control viral replication. Impaired antigen presentation and costimulation further complicate generation of effective cellular and humoral immune responses by aging Tɫ cell populations. Dashed lines indicate the probable contributions of SARS-CoV-2 infection to these age-related immunological alterations. CD: cluster of differentiation DC: dendritic cell DN: double negative GM-CSF: granulocyte–macrophage colony-stimulating factor HLA-DR: human leukocyte antigen – DR isotype IFN-I: type-I interferon PD-1: Programmed Death 1 Th: helper T TIM-3: T cell immunoglobulin mucin domain-3 TLR: toll-like receptor Treg: regulatory T

Dendritic cells (DCs) are the cellular source of PRRs and type-I IFNs. Plasmacytoid DCs (pDC) are particularly essential in development of primary nonspecific antiviral responses via viral recognition, and restriction of viral replication by inducing cytotoxic and T-helper (Th) cells with both antigen presentation and IFN-gamma secretion [42]. Number of pDCs were found to be selectively decreased in senescence process [43] (Fig.  2 ).

Macrophages and monocytes

Macrophages with their balancing and orchestrating properties are the central cells of the immune system. Their substantial functional alteration with aging which is termed as “macrophaging” has a hand in inflammaging and is largely responsible for impaired immune responses [44]. Macrophaging is characterized with weakened antigen presentation and impaired migration, phagocytosis, and production of certain chemotactic factors [45]. Macrophages bear different phenotypic features and functional properties that are shaped under the effect of multiple signals received from the microenvironment in which they are located [46]. The oxidative burden of aging and the management of its cumulative stress mainly via stress hormones and other neuroendocrine factors, appear to be the pivotal determinants of the changes in tissue architecture and signaling pathways [14, 47].

Another proposed theory is that macrophages, particularly alveolar macrophages being an expressor of ACE2 and transmembrane protease/serine subfamily 2 (TMPRSS2), may act as a reservoir facilitating the invasion of SARS-CoV-2 in the lungs, and its migration to other tissues, although it is not clear whether they allow viral replication. The increase in the number of alveolar macrophages and their dysfunctional alterations in aging-related diseases which have a chronic inflammatory pathogenesis such as diabetes and heart failure, and the more severe course of COVID-19 in these patient groups might be clues supporting this theory [48].

Monocytes are the circulating pool of tissue-resident APCs and are among the main contributors to the systemic inflammatory milieu determined by serum cytokine levels. Older individuals had lower expression of co-stimulatory CD40 molecule on their monocytes which impairs their trigger mission to proceed T- and B-cell responses [32]. Monocytes, grouped as classical (CD14 ++ CD16 − ), intermediate or transitional (CD14 ++ CD16 + ), and non-classical (CD14 + CD16 ++ ) subtypes, have different certain properties in terms of their maturity and immune response behaviors [49]. The percentage of non-classical (inflammatory) monocytes increase with aging [50] and they are known to be the group of monocytes that demonstrate cellular senescence-like properties [51]. The proportion of intermediate and non-classical monocytes was found to be significantly higher in COVID-19 patients and their higher percentages were correlated with disease severity [38, 52]. Whereas the study by Schulte-Schrepping et al. underlined a particular depletion of non-classical monocytes with an upregulated expression of tissue infiltration and retention markers (CD69 and CD226) in severe COVID-19 [53]. A significant decrease in transitional and non-classical monocytes in peripheral blood [54] together with the significant abundance of these monocyte subsets in bronchoalveolar samples [54, 55] of COVID-19 cases with increasing severity was also reported. Taken together, these studies seem to tell different parts of the same story, most likely due to the differences in the timing of sample collection of the studies. Although it would be possible to understand the exact situation only with further studies.

The peculiar immune-dysregulation pattern in most of the severe COVID-19 patients was distinctive with hypersecretion of IL-6 by monocytes despite diminished antigen presentation [56]. The prevailing conclusion from many other studies for the cytokine storm of COVID-19 is that the higher the IL-6 secretion by mainly monocytes, the more severe the clinical picture [52, 54, 57, 58]. High IL-6 levels associated with lowered expression of HLA-DR molecule by monocytes which was shown to be reversed by IL-6 blockage [56]. This situation constitutes an important weak spot of the immune system in coping with SARS-CoV-2 due to its disrupting of the development of an effective adaptive immune response and its negative correlation with lymphopenia (Fig.  2 ).

The fact that the alterations in monocytes with aging demonstrate sex-dependent diversity to the detriment of males [49, 59] not only explains the higher predisposition of aged men to diseases with chronic inflammatory pathogenesis such as cardiovascular disease but also overlaps with the higher COVID-19-related mortality risk of male sex [60].

Overall, being pivotal elements of innate immunity, monocytes and macrophages are of special importance for intricate interrelations of cellular senescence-inflammaging- and immunosenescence [49, 51, 57] and therefore the emergence of cytokine storm which is the characteristic pathophysiology in severe COVID-19 [57, 61]. Since they constitute both the very first line of defense in innate immunity and the regulatory cells for the adaptive immunity to generate specific immune response, monocytes and macrophages appear to be decisive for the severity of the clinical picture [62]. They play the leading role in both mechanisms that lead COVID-19 patients to respiratory failure: either macrophage activation syndrome [56, 63] or the unique immune dysregulation pattern characterized by monocyte hyperactivation and increased IL-6 secretion despite defective antigen presentation [56]. In addition, monocytes, through their interactions with platelets, play a critical role in the hypercoagulability and associated complications seen in severe disease [64].

Adaptive immunity (T- and B-cells)

Adaptive immune system which has the aptitude to develop superbly specific immune responses through its cell-mediated and humoral arms in cooperation with innate immunity weakens with aging. As expected, age-related deterioration in antigen presentation and preceding steps also blunts T-cell activation and expansion [31]. Increase in memory cells and decrease in naïve cells are the fundamental alterations of T lymphocytes in the course of immunosenescence [65]. Age-related thymic involution and functional impairment of its remaining reserve do not merely result in decreased naïve T-cell production, but also lower inducible regulatory T (Treg) cells and anti-inflammatory cytokine secretion [66] (Fig.  2 ). As thymus size and function are controlled by multiple factors like sex hormones, stress factors, metabolic hormones and adiposity, these changes might appear at varying rates between individuals [66] and contribute to inflammaging, impair effective immune responses to novel antigens and vaccines in older adults whereas memory responses are preserved [30]. Besides, costimulatory molecule CD28 expression decreases and telomere shortening is observed in senescent T-cells [67]. CD28 loss is characterized by inability of senescent T-cells to proliferate due to decreased telomerase activity, and nonspecific cytotoxicity in a manner like Natural Killer (NK) cells via recognition of NK-Cell receptors [68]. Therefore, senescent T lymphocyte repertoire is already disadvantageous in dealing with SARS-CoV-2 [25]. On top of that, in case of severe COVID-19 characterized by uncontrolled inflammatory cytokine release and lymphocytopenia [38], granulocyte–macrophage colony-stimulating factor-overexpressing pathogenic CD4 + Th1 cells, activated cytotoxic CD8 + T-cells and CD28 − NK-like T-cells were shown to have significantly increased proportion and so contributed to inflammatory damage by migration to lungs and other tissues and triggering further cytokine secretion [52, 54, 69]. T-cell exhaustion which means reduced functionality is another indicator of immunosenescence [25] and T-cell exhaustion markers PD-1 and TIM3 are expressed in higher levels with increasing COVID-19 severity [52, 70] (Fig.  2 ).

Vitamin D insufficiency is known to be associated with increased susceptibility to upper respiratory infections and several COVID-19 risk factors [71�]. Age-related hypovitaminosis D due to both its decreased production in the aging-skin and diminished bioavailability has negative effects on immunomodulation like dysregulation of T cell-driven inflammation via Treg cells [71].

In addition to disturbance of interactions with T-cells and innate immunity, B-cells are also altered during immunosenescence in terms of their subtype proportions and functions: Naïve B-cells decrease in number, their class-switching and somatic hypermutation functions are impaired, and age-associated B-cells (ABCs) which constitute an atypical subset of memory B-cells accumulate [25, 74]. Therefore, specific antibody production in response to first encounter with a new pathogen or vaccine fails and clonally expanded B-cells enhance the chronic inflammation of aging [74, 75]. Moreover, obesity-associated chronic inflammation, which imitates inflammaging, is an important risk factor for accelerated B-cell aging [76]. In the course of severe COVID-19, number of B-cells and plasmablasts was found to be increased, however it was not coupled with an increased immunoglobulin production [38]. Older COVID-19 patients demonstrated augmentation of age-related changes in B-cell subtypes: decreased naïve B-cells and increased ABCs [25] (Fig.  2 ). Novel data about sex-specific changes in immune aging revealed that B-cell specific genes were inactivated in older males whereas activated in females [59]. This finding is noteworthy as it overlaps with the knowledge of the more severe disease course and increased mortality rate of males in COVID-19 [60].

Diabetes affects how the body regulates blood glucose levels. Insulin helps to reduce levels of blood glucose whereas glucagon’s role is to increase blood glucose levels.

In people without diabetes, insulin and glucagon work together to keep blood glucose levels balanced.

In diabetes, the body either doesn’t produce enough insulin or doesn’t respond properly to insulin causing an imbalance between the effects of insulin and glucagon.

In type 1 diabetes , the body isn’t able to produce enough insulin and so blood glucose becomes too high unless insulin is injected.

In type 2 diabetes , the body is unable to respond effectively to insulin, which can also result in higher than normal blood glucose levels. Medications for type 2 diabetes include those which help to increase insulin sensitivity, those which stimulate the pancreas to release more insulin and other medications which inhibit the release of glucagon.


The names somatotropin (STH) or somatotropic hormone refer to the growth hormone produced naturally in animals and extracted from carcasses. Hormone extracted from human cadavers is abbreviated hGH. The main growth hormone produced by recombinant DNA technology has the approved generic name (INN) somatropin and the brand name Humatrope, [4] and is properly abbreviated rhGH in the scientific literature. Since its introduction in 1992 Humatrope has been a banned sports doping agent, [5] and in this context is referred to as HGH.

Gene Edit

Genes for human growth hormone, known as growth hormone 1 (somatotropin pituitary growth hormone) and growth hormone 2 (placental growth hormone growth hormone variant), are localized in the q22-24 region of chromosome 17 [6] [7] and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity.

Structure Edit

The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of 22,124 daltons. The structure includes four helices necessary for functional interaction with the GH receptor. It appears that, in structure, GH is evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between growth hormone from different species, only human and Old World monkey growth hormones have significant effects on the human growth hormone receptor. [8]

Several molecular isoforms of GH exist in the pituitary gland and are released to blood. In particular, a variant of approximately 20 kDa originated by an alternative splicing is present in a rather constant 1:9 ratio, [9] while recently an additional variant of

23-24 kDa has also been reported in post-exercise states at higher proportions. [10] This variant has not been identified, but it has been suggested to coincide with a 22 kDa glycosylated variant of 23 kDa identified in the pituitary gland. [11] Furthermore, these variants circulate partially bound to a protein (growth hormone-binding protein, GHBP), which is the truncated part of the growth hormone receptor, and an acid-labile subunit (ALS).

Regulation Edit

Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus. These cells release the peptides growth hormone-releasing hormone (GHRH or somatocrinin) and growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal venous blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion. [12]

Somatotropic cells in the anterior pituitary gland then synthesize and secrete GH in a pulsatile manner, in response to these stimuli by the hypothalamus. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep with plasma levels of 13 to 72 ng/mL. [13] Otherwise there is wide variation between days and individuals. Nearly fifty percent of GH secretion occurs during the third and fourth NREM sleep stages. [14] Surges of secretion during the day occur at 3- to 5-hour intervals. [3] The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL. [15] Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night. [13] Additional analysis of the pulsatile profile of GH described in all cases less than 1 ng/ml for basal levels while maximum peaks were situated around 10-20 ng/mL. [16] [17]

A number of factors are known to affect GH secretion, such as age, sex, diet, exercise, stress, and other hormones. [3] Young adolescents secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at the rate of about 400 μg/day. [18] Sleep deprivation generally suppresses GH release, particularly after early adulthood. [19]

Stimulators [ quantify ] of growth hormone (GH) secretion include:

  • Peptide hormones
      (somatocrinin) through binding to the growth hormone-releasing hormone receptor (GHRHR) [20] through binding to growth hormone secretagogue receptors (GHSR) [21]
    • Increased androgen secretion during puberty (in males from testes and in females from adrenal cortex) and DHEA

    Inhibitors [ quantify ] of GH secretion include:

      (somatostatin) from the periventricular nucleus[32]
    • circulating concentrations of GH and IGF-1 (negative feedback on the pituitary and hypothalamus) [3][23][33]

    In addition to control by endogenous and stimulus processes, a number of foreign compounds (xenobiotics such as drugs and endocrine disruptors) are known to influence GH secretion and function. [34]

    Function Edit

    Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones, GH acts by interacting with a specific receptor on the surface of cells.

    Increased height during childhood is the most widely known effect of GH. Height appears to be stimulated by at least two mechanisms:

    1. Because polypeptide hormones are not fat-soluble, they cannot penetrate cell membranes. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. [35] Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.
    2. GH also stimulates, through the JAK-STAT signaling pathway, [35] the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. [36] The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it what appears to be both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.

    In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:

    • Increases calcium retention, [37] [citation needed] and strengthens and increases the mineralization of bone
    • Increases muscle mass through sarcomerehypertrophy
    • Promotes lipolysis
    • Increases protein synthesis
    • Stimulates the growth of all internal organs excluding the brain
    • Plays a role in homeostasis
    • Reduces liver uptake of glucose
    • Promotes gluconeogenesis in the liver [38]
    • Contributes to the maintenance and function of pancreatic islets
    • Stimulates the immune system
    • Increases deiodination of T4 to T3 [39]

    GH has a short biological half-life of about 10 to 20 minutes. [40] [41]

    Excess Edit

    The most common disease of GH excess is a pituitary tumor composed of somatotroph cells of the anterior pituitary. These somatotroph adenomas are benign and grow slowly, gradually producing more and more GH. For years, the principal clinical problems are those of GH excess. Eventually, the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement.

    Prolonged GH excess thickens the bones of the jaw, fingers and toes, resulting heaviness of the jaw and increased size of digits, referred to as acromegaly. Accompanying problems can include sweating, pressure on nerves (e.g. carpal tunnel syndrome), muscle weakness, excess sex hormone-binding globulin (SHBG), insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.

    GH-secreting tumors are typically recognized in the fifth decade of life. It is extremely rare for such a tumor to occur in childhood, but, when it does, the excessive GH can cause excessive growth, traditionally referred to as pituitary gigantism.

    Surgical removal is the usual treatment for GH-producing tumors. In some circumstances, focused radiation or a GH antagonist such as pegvisomant may be employed to shrink the tumor or block function. Other drugs like octreotide (somatostatin agonist) and bromocriptine (dopamine agonist) can be used to block GH secretion because both somatostatin and dopamine negatively inhibit GHRH-mediated GH release from the anterior pituitary. [ citation needed ]

    Deficiency Edit

    The effects of growth hormone (GH) deficiency vary depending on the age at which they occur. Alterations in somatomedin can result in growth hormone deficiency with two known mechanisms failure of tissues to respond to somatomedin, or failure of the liver to produce somatomedin. [42] Major manifestations of GH deficiency in children are growth failure, the development of a short stature, and delayed sexual maturity. In adults, somatomedin alteration contributes to increased osteoclast activity, resulting in weaker bones that are more prone to pathologic fracture and osteoporosis. [42] However, deficiency is rare in adults, with the most common cause being a pituitary adenoma. [43] Other adult causes include a continuation of a childhood problem, other structural lesions or trauma, and very rarely idiopathic GHD. [43]

    Adults with GHD "tend to have a relative increase in fat mass and a relative decrease in muscle mass and, in many instances, decreased energy and quality of life". [43]

    Diagnosis of GH deficiency involves a multiple-step diagnostic process, usually culminating in GH stimulation tests to see if the patient's pituitary gland will release a pulse of GH when provoked by various stimuli.

    Quality of life Edit

    Several studies, primarily involving patients with GH deficiency, have suggested a crucial role of GH in both mental and emotional well-being and maintaining a high energy level. Adults with GH deficiency often have higher rates of depression than those without. [44] While GH replacement therapy has been proposed to treat depression as a result of GH deficiency, the long-term effects of such therapy are unknown. [44]

    Cognitive function Edit

    GH has also been studied in the context of cognitive function, including learning and memory. [45] GH in humans appears to improve cognitive function and may be useful in the treatment of patients with cognitive impairment that is a result of GH deficiency. [45]

    Replacement therapy Edit

    GH is used as replacement therapy in adults with GH deficiency of either childhood-onset or adult-onset (usually as a result of an acquired pituitary tumor). In these patients, benefits have variably included reduced fat mass, increased lean mass, increased bone density, improved lipid profile, reduced cardiovascular risk factors, and improved psychosocial well-being.

    Other approved uses Edit

    GH can be used to treat conditions that produce short stature but are not related to deficiencies in GH. However, results are not as dramatic when compared to short stature that is solely attributable to deficiency of GH. Examples of other causes of shortness often treated with GH are Turner syndrome, chronic kidney failure, Prader–Willi syndrome, intrauterine growth restriction, and severe idiopathic short stature. Higher ("pharmacologic") doses are required to produce significant acceleration of growth in these conditions, producing blood levels well above normal ("physiologic"). Despite the higher doses, side-effects during treatment are rare, and vary little according to the condition being treated. [ citation needed ]

    One version of rHGH has also been FDA approved for maintaining muscle mass in wasting due to AIDS. [46]

    Off-label use Edit

    Off-label prescription of HGH is controversial and may be illegal. [47]

    Claims for GH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study wherein GH was used to treat 12 men over 60. [48] At the conclusion of the study, all the men showed statistically significant increases in lean body mass and bone mineral density, while the control group did not. The authors of the study noted that these improvements were the opposite of the changes that would normally occur over a 10- to 20-year aging period. Despite the fact the authors at no time claimed that GH had reversed the aging process itself, their results were misinterpreted as indicating that GH is an effective anti-aging agent. [49] [50] [51] This has led to organizations such as the controversial American Academy of Anti-Aging Medicine promoting the use of this hormone as an "anti-aging agent". [52]

    A Stanford University School of Medicine meta-analysis of clinical studies on the subject published in early 2007 showed that the application of GH on healthy elderly patients increased muscle by about 2 kg and decreased body fat by the same amount. [49] However, these were the only positive effects from taking GH. No other critical factors were affected, such as bone density, cholesterol levels, lipid measurements, maximal oxygen consumption, or any other factor that would indicate increased fitness. [49] Researchers also did not discover any gain in muscle strength, which led them to believe that GH merely let the body store more water in the muscles rather than increase muscle growth. This would explain the increase in lean body mass.

    GH has also been used experimentally to treat multiple sclerosis, to enhance weight loss in obesity, as well as in fibromyalgia, heart failure, Crohn's disease and ulcerative colitis, and burns. GH has also been used experimentally in patients with short bowel syndrome to lessen the requirement for intravenous total parenteral nutrition.

    In 1990, the US Congress passed an omnibus crime bill, the Crime Control Act of 1990, that amended the Federal Food, Drug, and Cosmetic Act, that classified anabolic steroids as controlled substances and added a new section that stated that a person who "knowingly distributes, or possesses with intent to distribute, human growth hormone for any use in humans other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services" has committed a felony. [53] [54]

    The Drug Enforcement Administration of the US Department of Justice considers off-label prescribing of HGH to be illegal, and to be a key path for illicit distribution of HGH. [47] This section has also been interpreted by some doctors, most notably [55] the authors of a commentary article published in the Journal of the American Medical Association in 2005, as meaning that prescribing HGH off-label may be considered illegal. [56] And some articles in the popular press, such as those criticizing the pharmaceutical industry for marketing drugs for off-label use (with concern of ethics violations) have made strong statements about whether doctors can prescribe HGH off-label: "Unlike other prescription drugs, HGH may be prescribed only for specific uses. U.S. sales are limited by law to treat a rare growth defect in children and a handful of uncommon conditions like short bowel syndrome or Prader-Willi syndrome, a congenital disease that causes reduced muscle tone and a lack of hormones in sex glands." [57] [58] At the same time, anti-aging clinics where doctors prescribe, administer, and sell HGH to people are big business. [57] [59] In a 2012 article in Vanity Fair, when asked how HGH prescriptions far exceed the number of adult patients estimated to have HGH-deficiency, Dragos Roman, who leads a team at the FDA that reviews drugs in endocrinology, said "The F.D.A. doesn't regulate off-label uses of H.G.H. Sometimes it's used appropriately. Sometimes it's not." [59]

    Side effects Edit

    Injection-site reaction is common. More rarely, patients can experience joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes. [49] In some cases, the patient can produce an immune response against GH. GH may also be a risk factor for Hodgkin's lymphoma. [60]

    One survey of adults that had been treated with replacement cadaver GH (which has not been used anywhere in the world since 1985) during childhood showed a mildly increased incidence of colon cancer and prostate cancer, but linkage with the GH treatment was not established. [61]

    The first description of the use of GH as a doping agent was Dan Duchaine's "Underground Steroid handbook" which emerged from California in 1982 it is not known where and when GH was first used this way. [62]

    Athletes in many sports have used human growth hormone in order to attempt to enhance their athletic performance. Some recent studies have not been able to support claims that human growth hormone can improve the athletic performance of professional male athletes. [63] [64] [65] Many athletic societies ban the use of GH and will issue sanctions against athletes who are caught using it. However, because GH is a potent endogenous protein, it is very difficult to detect GH doping. In the United States, GH is legally available only by prescription from a medical doctor.

    To capitalize on the idea that GH might be useful to combat aging, companies selling dietary supplements have websites selling products linked to GH in the advertising text, with medical-sounding names described as "HGH Releasers". Typical ingredients include amino acids, minerals, vitamins, and/or herbal extracts, the combination of which are described as causing the body to make more GH with corresponding beneficial effects. In the United States, because these products are marketed as dietary supplements, it is illegal for them to contain GH, which is a drug. Also, under United States law, products sold as dietary supplements cannot have claims that the supplement treats or prevents any disease or condition, and the advertising material must contain a statement that the health claims are not approved by the FDA. The FTC and the FDA do enforce the law when they become aware of violations. [66]

    In the United States, it is legal to give a bovine GH to dairy cows to increase milk production, and is legal to use GH in raising cows for beef see article on Bovine somatotropin, cattle feeding, dairy farming and the beef hormone controversy.

    The use of GH in poultry farming is illegal in the United States. [67] [68] Similarly, no chicken meat for sale in Australia is administered hormones. [69]

    Several companies have attempted to have a version of GH for use in pigs (porcine somatotropin) approved by the FDA but all applications have been withdrawn. [70] [71]

    The identification, purification and later synthesis of growth hormone is associated with Choh Hao Li. Genentech pioneered the first use of recombinant human growth hormone for human therapy in 1981.

    Prior to its production by recombinant DNA technology, growth hormone used to treat deficiencies was extracted from the pituitary glands of cadavers. Attempts to create a wholly synthetic HGH failed. Limited supplies of HGH resulted in the restriction of HGH therapy to the treatment of idiopathic short stature. [72] Very limited clinical studies of growth hormone derived from an Old World monkey, the rhesus macaque, were conducted by John C. Beck and colleagues in Montreal, in the late 1950s. [73] The study published in 1957, which was conducted on "a 13-year-old male with well-documented hypopituitarism secondary to a crainiophyaryngioma," found that: "Human and monkey growth hormone resulted in a significant enhancement of nitrogen storage . (and) there was a retention of potassium, phosphorus, calcium, and sodium. . There was a gain in body weight during both periods. . There was a significant increase in urinary excretion of aldosterone during both periods of administration of growth hormone. This was most marked with the human growth hormone. . Impairment of the glucose tolerance curve was evident after 10 days of administration of the human growth hormone. No change in glucose tolerance was demonstrable on the fifth day of administration of monkey growth hormone." [73] The other study, published in 1958, was conducted on six people: the same subject as the Science paper an 18-year-old male with statural and sexual retardation and a skeletal age of between 13 and 14 years a 15-year-old female with well-documented hypopituitarism secondary to a craniopharyngioma a 53-year-old female with carcinoma of the breast and widespread skeletal metastases a 68-year-old female with advanced postmenopausal osteoporosis and a healthy 24-year-old medical student without any clinical or laboratory evidence of systemic disease. [74]

    In 1985, unusual cases of Creutzfeldt–Jakob disease were found in individuals that had received cadaver-derived HGH ten to fifteen years previously. Based on the assumption that infectious prions causing the disease were transferred along with the cadaver-derived HGH, cadaver-derived HGH was removed from the market. [18]

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    15.1: Age Related Changes to the Endocrine System - Biology

    Everyone's body undergoes changes, some natural and some not, that can affect the way the endocrine system works. Some of the factors that affect endocrine organs include puberty, aging, pregnancy, the environment, genetics and certain diseases and medications, including naturopathic medicine, herbal supplements, and prescription medicines such as opioids or steroids.


    Despite age-related changes, the endocrine system functions well in most older people. However, some changes occur because of either damage to cells during the aging process or medical issues that the aging body accumulates, or genetically programmed cellular changes. These changes may alter the following:

    • hormone production and secretion
    • hormone metabolism (how quickly hormones are broken down and leave the body)
    • hormone levels circulating in blood
    • target cell or target tissue response to hormones
    • rhythms in the body, such as the menstrual cycle

    For example, increasing age is thought to be related to the development of type 2 diabetes, especially in people who might be at risk for this disorder. The aging process affects nearly every gland. With increasing age, the pituitary gland (located in the brain) can become smaller and may not work as well, although may provide sufficient hormonal signaling for continuity of life. For example, production of growth hormone might decrease, which is likely not a priority in an aging individual this is also an example of genetic programming that we have evolved as species to adapt to. Decreased growth hormone levels in older people might lead to problems such as decreased lean muscle, decreased heart function, and osteoporosis. Aging affects a woman's ovaries and results in menopause, usually between 50 and 55 years of age. In menopause, the ovaries stop making estrogen and progesterone and no longer have a store of eggs. When this happens, menstrual periods stop.

    Diseases and Conditions

    Chronic diseases and other conditions may affect endocrine system function in several ways. After hormones produce their effects at their target organs, they are broken down (metabolized) into inactive molecules. The liver and kidneys are the main organs that break down hormones. The ability of the body to break down hormones may be decreased in people who have chronic heart, liver, or kidney disease.

    Abnormal endocrine function can result from:

    • congenital (birth) or genetic defects (see section on Genetics below)
    • surgery, radiation, or some cancer treatments
    • traumatic injuries
    • cancerous and non-cancerous tumors
    • infection
    • autoimmune destruction (when the immune system turns against the body's own organs and causes damage)
    • medications or supplements

    In general, abnormal endocrine function creates a hormone imbalance typified by too much or too little of a hormone. The underlying problem might be due to an endocrine gland making too much or too little of the hormone, or to a problem breaking down the hormone.


    Physical or mental stressors can trigger a stress response. The stress response is complex and can influence heart, kidney, liver, and endocrine system function. Many factors can start the stress response, but physical stressors are most important. For the body to respond to, and cope with physical stress, the adrenal glands make more cortisol. If the adrenal glands do not respond, this can be a life-threatening problem. Some medically important factors causing a stress response are:

    • trauma (severe injury) of any type
    • severe illness or infection
    • intense heat or cold
    • surgical procedures
    • serious diseases
    • allergic reactions

    Other types of stress include emotional, social, or economic, but these usually do not require the body to produce high levels of cortisol to survive the stress.

    Environmental Factors

    An environmental endocrine disrupting chemical (EDC) is a substance outside of the body that may interfere with the normal function of the endocrine system. Some EDCs mimic natural hormone binding at the target cell receptor. (Binding occurs when a hormone attaches to a cell receptor, a part of the cell designed to respond to that particular hormone.) EDCs can start the same processes that the natural hormone would start. Other EDCs block normal hormone binding and thereby prevent the effects of the natural hormones. Still other EDCs can directly interfere with the production, storage, release, transport, or elimination of natural hormones in the body. This can greatly affect the function of certain body systems.

    EDCs can affect people in many ways:

    • disrupted sexual development
    • decreased fertility
    • birth defects
    • reduced immune response
    • neurological and behavioral changes, including reduced ability to handle stress


    Your endocrine system can be affected by genes. Genes are units of hereditary information passed from parent to child. Genes are contained in chromosomes. The normal number of chromosomes is 46 (23 pairs). Sometimes extra, missing, or damaged chromosomes can result in diseases or conditions that affect hormone production or function. The 23rd pair, for example, is the sex chromosome pair. A mother and father each contribute a sex chromosome to the child. Girls usually have two X chromosomes while boys have one X and one Y chromosome. Sometimes, however, a chromosome or piece of a chromosome may be missing. In Turner syndrome, only one normal X chromosome is present and this can cause poor growth and a problem with how the ovaries function. In another example, a child with Prader-Willi syndrome may be missing all or part of chromosome 15, which affects growth, metabolism, and puberty. Your genes also may place you at increased risk for certain diseases, such as breast cancer. Women who have inherited mutations in the BRCA1 or BRCA2 gene face a much higher risk of developing breast cancer and ovarian cancer compared with the general population.

    If you suspect hormone or endocrine-related problems get help from an endocrinologist near you.

    Chapter Overview: Endocrine System

    In this chapter, you will learn about the endocrine system, a system of glands that secrete hormones that regulate many of the body’s functions. Specifically, you will learn about:

    • The glands that make up the endocrine system , and how hormone s act as chemical messengers in the body.
    • The general types of endocrine system disorders.
    • The types of endocrine hormones — including steroid hormones (such as sex hormones) and non-steroid hormones (such as insulin) — and how they affect the functions of their target cells by binding to different types of receptor proteins.
    • How the levels of hormones are regulated mostly through negative, but sometimes through positive, feedback loops.
    • The master gland of the endocrine system, the pituitary gland , which controls other parts of the endocrine system through the hormones that it secretes, as well as how the pituitary itself is regulated by hormones secreted from the hypothalamus of the brain.
    • The thyroid gland and its hormones — which regulate processes including metabolism and calcium homeostasis — how the thyroid is regulated, and the disorders that can occur when there are problems in thyroid hormone regulation (such as hyperthyroidism and hypothyroidism).
    • The adrenal glands , which secrete hormones that regulate processes such as metabolism, electrolyte balance, responses to stress, and reproductive functions, and the disorders that can occur when there are problems in adrenal hormone regulation, such as Cushing’s syndrome and Addison’s disease.
    • The pancreas , which secretes hormones that regulate blood glucose levels (such as insulin), and disorders of the pancreas and its hormones, including diabetes .

    Later chapters in this book will discuss the glands and hormones involved in the reproductive and immune systems in more depth.

    As you read this chapter, think about the following questions:

    1. Why can hormones have such broad range effects on the body, as we see in PCOS?
    2. Which hormones normally regulate blood glucose? How is this related to diabetes?
    3. What are androgens? How do you think their functions relate to some of the symptoms that Gabrielle is experiencing?

    Pituitary Blood Vessel Development

    Part of pituitary Arterial supply Systemic venous return Portal system return
    Pars anterior and pars intermedia From carotid: a bilateral supply, usually one on each side, sometimes more than one Systemic veins to cavernous sinus following the course of the bilateral arteries Contribute blood to portal vessels
    Pars tuberalis From circle of Willis by small branches around the outside of the stalk Small systemic veins corresponding to the arteries Contributes blood to the portal vessels
    Pars posterior By branches from the bilateral supply from the carotids By small systemic venous branches following the course ofthe arterial twigs Contributes blood to the portal vessels by fine channels opening into them below their heavy glial sleeves

    pars distalis - vascularized by hypophysial portal vessels

    A study in rats has identified the role of a known regulator of blood vessel development (Vascular Endothelial Growth Factor, VEGF) in the development of the pituitary portal vascular system. Δ] "The primary capillaries extended along the developing pars tuberalis, whereas the portal vessels penetrated into the pars distalis at E15.5 (rat) and subsequently expanded into the lobe to connect with the secondary capillary plexus, emerging in the pars distalis. . study suggests that VEGF-A (Vascular Endothelial Growth Factor A) is involved in the development of the primary capillaries and in the vascularization of the pars distalis, but not in the portal vessels since the formation of portal vessels begins at E13.5 (rat), before the appearance of VEGF-A in the rostral region of the pars distalis."

    The pars distalis is vascularized by hypophysial portal vessels that arise from the capillary beds in the median eminence of the hypothalamus (Murakami et al. 1987), and this hypophyseal portal system provides an important link for carrying hormonal information from the central nervous system to the pituitary. The capillaries of the pituitary gland are characterized by richly fenestrated endothelia.