Over the past several decades, hormone replacement therapy (HRT) has been concurrently at the forefront of medical science, and the focal point of public interest, while being effectively prepared and administered to millions of patients. While researchers and physicians have been making great strides in knowledge and treatment, Oprah has talked about it, Suzanne Summers has written about it, and Empower Pharmacy has provided HRT as a means help patients get back on the road to good health and wellness.
In general, HRT is the method used to treat the symptoms of menopause and other hormonal imbalances in both sexes. However, HRT is most often spoken of (and will be so here) as female hormone replacement, which is traditionally contrasted with testosterone replacement therapy (TRT). Nevertheless, it should be made very clear that both HRT and TRT may be required by and administered to either gender. More specifically, custom HRT is a method of providing specific hormones (which often involves combinations of hormones) in the exact dosages required to meet a patient’s uniquely individual needs. The method by which hormones are customized is called ‘compounding’.1
In the 1930s, Canadian researcher, biochemist, educator, and co-discoverer of insulin, James Bertram Collip turned his attention to endocrinology.2 It was during this decade that he pioneered the isolation and study of the ovarian and gonadotrophic hormones, more specifically by extracting estrogen from the urine of pregnant women. Although initially used to treat menopause symptoms such as hot flashes and vaginal dryness, by the 1960s Collip’s findings had captured the imagination of millions.
Since the 1962 introduction of Premarin, the first estrogen pill, manufacturers of sex hormones have generated a marketing and cultural suspicion that hormone replacement therapy may do harm than good. Estrogen's heyday started with a 1966 book for the masses, titled ’Feminine Forever’ by Manhattan gynecologist Robert Wilson whose strong financial ties to hormone makers gave him a clearly biased perspective. The book shocked the world by calling menopausal women "castrates" if they didn't take hormones. Through his nationwide tours Wilson won women over with scientific-sounding promises of youth, beauty, and better sex. The U.S. Food and Drug Administration (FDA) banned Wilson from certain types of research for making such unsubstantiated claims. After the book, millions of postmenopausal women were taking the "Youth Pill" for all of life’s ills. Other books and magazine articles followed, pushing estrogen as a salvation for older women and suggesting that it might prevent cancer. Hormone manufacturers even produced films to educate doctors about hormone treatments, many of which contained utter misinformation, some of which still persists today. All media forms falsely reported that hormones improved every woman’s quality of life. However, in the later part of the 1990’s, a number of women were questioning the use of HRT. Some of the common questions that arose were: “Did all women need it?” and “Why were all women put on the same dose and not different dosages?” In 2002, the results of an extensive women’s study by the Women’s Health Initiative (WHI) looked at the effects of HRT (both Premarin and Prempro). Its findings overwhelmed the medical community by establishing that HRT in fact did not decrease a woman’s chances of getting heart disease, but rather definitively increased her risk of blood clotting, stroke, and breast cancer.3
Today we are far more knowledgeable regarding HRT diagnoses, and discerning which populations should receive and benefit from it. Lastly, unlike HRT of the past, modern day HRT administration is followed up by continuous monitoring and the repeated tweaking of hormonal levels to provide the necessary safeguards.
Produced by the major endocrine glands (pituitary, pineal, thymus, thyroid, adrenals, and pancreas) as well as within the sex organs, hormones are your body's chemical messengers. They travel throughout the bloodstream to specific tissues and organs, where they work at varying speeds, inducing many different physiological processes central to which are: growth and development; metabolism; sexual functions; reproduction; and mood.
Furthermore, the male testes and the female ovaries produce largely gender-specific hormones, which perform an expansive range of functions. Collectively, these powerful chemicals are required in only miniscule amounts, yet incite major changes within cells, tissues, and organs throughout the body. The addition of too much or too little of a certain hormone can have serious consequences. For this reason, hormone therapy should only be conducted under physician supervision, after laboratory tests have been used to accurately measure the hormonal levels within your blood, urine, or saliva.
After puberty androgens, specifically testosterone, play a role in the regulation of the sex drive within both genders. Concordantly, deficiencies in testosterone or estrogen (as well as progesterone and DHEA which are also multi-faceted hormones) may cause a drop in sexual desire, whereas excessive amounts of these hormones may heighten sexual interest.4
Testosterone is a hormone produced within the testicles via a joint process, which also includes the endocrine system and the pituitary gland. This system is collectively known as the Hypothalamic-Pituitary-Testicular axis (HPTA).5 Testosterone serves as the male body’s primary natural hormone, and is largely responsible for the proper development of male sexual characteristics. Although often referred to as a sex hormone, testosterone actually governs several areas within the body including a man’s development from birth onward with responsibility for everything from initial structural gender differentiation, through pubertal changes and male potency (libido & sexual functioning), to the partitioning of bodily muscle and fat distribution.6 It is also an integral component in men’s sense of well-being, playing a major role in male physiological, biological, and sexual health, while influencing stress coping capacity,7 sperm production, mental acuity (clarity, memory & recall, concentration & focus),7 bone density,8 immune system support, and red blood cell production. Of course testosterone is present in both males and females; however, males typically produce between 4-7 mg per day, which is approximately ten times more than their estrogen-based female counterparts.
Estrogens are the sex hormones produced primarily by a female's ovaries that stimulate the growth of a girl's sex organs, her breasts, pubic hair, and other secondary sex characteristics. There are three basic estrogens, namely estrone (E1), estradiol (E2), and estriol (E3),9 however progesterone (another female-centric hormone) is often considered an estrogen as well.10 Collectively, these estrogens regulate a diverse array of chemically induced processes within the female body among which are the menstrual cycle, intercourse preparation and during intercourse functions, as well as impact mood, sleep quality, body fat levels, water retention, etc.11 As with testosterone, estrogen is present with both genders; women produce appreciatively more at approximately 0.5 mg daily.12 Aging, illness, and certain cancer treatments can adversely affect the body's delicate hormonal balance, causing changes in sexual interest and functioning.13 The most familiar of these changes occurs when a women go through menopause. Estrogen production drops throughout this process as women exit their child-bearing years.
However, in the majority of women, ovarian hormones don't appear to play a significant role in their sex drive. A 2012 study14 published in the Journal of Obstetrics and Gynecology showed that ovaries, i.e. estrogen production, may not play a pivotal role in sexual ideation and function among older women. This cross-sectional study involved analysis of 1,352 women (57 to 85 years of age) from the National Social Life, Health, and Aging Project compared women with previous bilateral oophorectomy (removal of one or both of the ovaries) with women who retained their ovaries. The primary outcome of interest was self-report of sexual ideation, chosen because having thoughts about sexual experiences is not prohibited by either a partner or a woman's own physical limitations. Three hundred fifty-six (25.8%) women reported previous bilateral oophorectomy. Even after adjusting for current hormone therapy, age, education, and race, no significant difference in the report of sexual ideation was found between groups.15
How Hormone Replacement Works
Hormone replacement therapy is the method used to treat not only the symptoms of menopause, but all other hormonal imbalances as well. A hormone will only act on a part of the body if it ‘fits’, and can therefore be thought of as a type of ‘key’. Its target site (such as a cell) has specially shaped receptors which are analogous to ‘locks’ on their cell walls. If the key(hormone) fits the lock (receptor site), then the hormone will work by impacting the target site (cell), and altering the function of its tissue and/or organ. The primary affected glands include:
- Pituitary gland - inside the brain, oversees the other glands and keeps hormone levels in check. It can also bring about a change in hormone production somewhere else in the system by releasing its own ‘stimulating’ hormones.
- Thyroid gland - inside the neck, controls the rate of metabolism.
- Parathyroid glands - inside the neck surrounding the thyroid gland, control the level of calcium in the bloodstream.
- Adrenal glands - atop each kidney, make a number of different hormones, such as adrenaline and cortisol in times of stress, as well as sex hormones.
- Pancreas - inside the abdomen, an organ of digestion which makes insulin to control the amount of sugar in the bloodstream.
- Ovaries - inside the female pelvis, make female sex hormones like estrogen.
- Testes - inside the male scrotum, make male sex hormones like testosterone.
Some common problems of the endocrine system that may be addressed by HRT include: diabetes- too much sugar in the blood caused by problems with insulin production; premenstrual syndrome- symptoms include cramping, bloating, breast tenderness and mood swings; and thyroid problems- when the gland is overactive (hyperthyroidism) or underactive (hypothyroidism).
The endocrine glands receive feedback from the hypothalamus - a small but important part of the brain which contains several small nuclei with a diversity of functions. It plays an important role in both the nervous and endocrine systems. All vertebrate brains contain a hypothalamus, which in humans, it is roughly the size of an almond and located just below the thalamus and right above the brain stem. Linked to another small and vital gland called the pituitary gland, the hypothalamus controls certain metabolic processes and other activities of the autonomic nervous system by synthesizing and secreting neurohormones, often called hypothalamic-releasing hormones. These hypothalamic releasing hormones control and regulate the major endocrine glands (pituitary, pineal, thymus, thyroid, adrenals, and pancreas) as well as within the sex organs (male testes and female ovaries). Hormones are your body's chemical messengers, they travel throughout the bloodstream to specific cells, tissues, and organs where they work at varying speeds inducing a wide range of homeostatic and other physiological processes central to which are:
- The release of 8 major hormones by the pituitary gland
- Growth and development
- Cellular repair
- Body temperature
- Hunger, thirst and food, and water intake
- Sexual behavior and reproductive functions
- Daily cycles in physiological state and behavior also known as circadian rhythm
- Mediation of emotional responses and mood
- Circulatory and respiratory function
The goal of HRT is to optimize function, prevent morbidity with aging, and to enhance quality of life. With proper modification, adjustment, and titration by an experienced anti-aging physician, the benefits of HRT far outweigh the risks. Anti-aging physicians remain steadfastly at the helm advancing hormone replacement therapy, thereby providing crucial research data to ultimately negate the controversy and confirm the safety and efficacy of HRT.
Restoring Hormonal Balance
Millions of women, from every age and background, experience some form of hormone-related health condition during their lifetimes. For many women, help comes in the form of hormone replacement therapy.
Hormones produced by our pharmacy have the exact same chemical structure as naturally occurring human hormones. Consequently, your body recognizes them and allows them to mimic the function of the hormones the body produces on its own. HRT may be useful for relieving the symptoms of a variety of conditions common among women of all ages, including:
- Premenstrual Syndrome (PMS)
- Irregular menstrual cycle
- Hot flashes
- Post-partum depression
- Decreased libido
- Weight gain
- Fibrocystic breasts
- Vaginal Dryness
- Painful sexual intercourse
- Sleep disturbances
- Night sweats
HRT replaces deficient hormones with those that are chemically identical to those that the body naturally produces,16 but which have declined due to aging or illness. HRT has improved the quality of life for millions of women and men who suffer from hormonal imbalance.171819 The ideal process for achieving hormonal balance includes: an assessment of hormone levels:16 complete evaluation of signs and symptoms; replacement of the deficient hormones in the most appropriate dose via the most effective route; and the monitoring to fine tuning of therapy. Estrogens, progesterone, and androgens are just the tip of the iceberg when it comes to achieving hormonal balance. Thyroid and adrenal function, as well as nutritional status, should also be evaluated and treated when indicated.
The uniqueness of each person makes it incumbent upon health care professionals and patients to work together to customize hormone therapy. Through this cooperation, hormones can be compounded in the required strengths and dosages, and administered via the most appropriate preparation to best meet each individual’s needs.
Oxytocin is a nonapeptide (nine amino acids) hormone secreted by the posterior pituitary. Oxytocin produces action both peripherally and in the brain. Oxytocin is released by males and females during orgasm and is considered by many to be the hormone of desire, social recognition and bonding. Oxytocin is primarily administered by injection or nasal spray because Chymotrypsin, present in the gastrointestinal tract, destroys oxytocin, rendering oral administration ineffective.20 Clinically, oxytocin is used most often to induce and strengthen labor and control postpartum bleeding. Intranasal preparations of oxytocin, used to stimulate postpartum milk ejection, are no longer manufactured in the US, so a compounding pharmacy is necessary for this preparation.
Oxytocin has action on uterine contraction, milk letdown, orgasm, sexual arousal, bonding and maternal behavior.21 For this reason, it is sometimes referred to as the "bonding hormone". There is some evidence that oxytocin promotes ethnocentric behavior, incorporating the trust and empathy of in-groups with their suspicion and rejection of outsiders.22 Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behavior.23
Oxytocin is a hormone produced mainly by the hypothalamus (an almond sized region of the brain) and is released either directly into the blood via the pituitary gland, or to other parts of the brain and spinal cord. Best known for its role in childbirth, oxytocin plays a vital role in triggering uterine contractions. Many times if contractions are not powerful enough to complete delivery the mother will be give oxytocin to help the labor process and contractions.24
Although Oxytocin is implicated in a variety of “non-social” behaviors, such as learning, anxiety, feeding and pain perception, it is Oxytocin’s roles in various social behaviors that have come to the fore recently. Oxytocin is important for social memory and attachment, sexual and maternal behavior, and aggression. Recent work implicates Oxytocin in human bonding and trust as well. Human disorders characterized by aberrant social interactions, such as autism and schizophrenia, may also involve Oxytocin expression.25
Oxytocin and Lactation
It has been postulated that a rise in the concentration of oxytocin causes contraction of cells around the alveoli and milk ducts, in preparation for suckling, and that lactation failure may result from insufficient oxytocin.26 When the infant is suckled, afferent impulses from sensory stimulation of nerve terminals in the areolas travel to the central nervous system where they promote the release of oxytocin from the posterior pituitary. In the woman oxytocin release is often associated with such stimuli as the sight or sound or even the thought of the infant indicating a large cerebral component in this "neuroendocrine reflex". The oxytocin is carried through the blood stream to the mammary gland where it interacts with specific receptors on myoepithelial cells, initiating their contraction and expelling milk from the alveoli into the ducts and sub-areolar sinuses. The passage of milk through the ducts allows free flow of milk to the nipple. The process by which milk is forcibly moved out of the alveoli is called milk ejection or let-down and is essential to milk removal from the lactating breast.27 Oxytocin nasal spray has been used successfully to help treat for "the let-down effect".28 There is speculation that in addition to facilitating lactation and the birthing process, the hormone facilitates the emotional bond between mother and child.29
Oxytocin and Autism
Oxytocin has recently received significant interest in the Autism community. Researchers have found that autistic children have lower plasma levels of oxytocin than those of other children. Oxytocin plays a role in social behavior, including but not limited to: repetitive behaviors, the desire to form social bonds, social recognition, processing social cues, regulated feeding, excessive grooming, stress response and being aloof.
One study, published in The Proceedings of the National Academy of Sciences, found that the hormone, given as an inhalant, generated increased activity in parts of the brain involved in social connection. Oxytocin facilitated social attunement, a process that makes the brain regions involved in social behavior and social cognition activate more for social stimuli (such as faces) and activate less for non-social stimuli (such as cars). This suggests not only that oxytocin can stimulate social brain areas, but also that in children with autism these brain regions are not irrevocably damaged but are plastic enough to be influenced.30313233343536
Oxytocin and Sexual Response
Recent studies show that Oxytocin is involved in multiple signaling pathways in the central and peripheral nerve system and mainly regulates the physiology and activity of reproduction, including male reproduction and sexual behavior. The roles of Oxytocin in penile erection are bio-phasic with proerectile effect in the central nerve system while peripherally inhibiting erection. Oxytocin also mediates ejaculation, post-ejaculatory detumescence and the post-orgasm refractory period.3738
Oxytocin has also become the subject of studies in female sexual dysfunction specifically difficulty achieving orgasm. Oxytocin increases sexual receptivity and counteracts impotence.39 Oxytocin can be used to help treat Female Orgasmic Disorder, Female Arousal Disorder or for those women who just desire a more powerful or multiple orgasms.40
Recent research has shown that oxytocin may have many other far-reaching effects particularly when it comes to relationships and emotional involvement. Oxytocin is the reason why we form all sorts of deep connections not only with our children, but with our partners, friends and even our pets and is often called the “bonding hormone”. Oxytocin also plays a huge role in the non-procreative aspects of sex.
Research has shown that for women, not only is oxytocin released during orgasm, it appears to be responsible for causing orgasms in the first place. Research indicates that oxytocin causes the nerves in the genitals to fire spontaneously, and this leads to powerful orgasms. In women, during orgasm, oxytocin levels increase significantly. During peak sexual arousal, if a woman’s brain is flooded with oxytocin, she may indeed be capable of multiple orgasms.41
Sometimes called “the cuddle hormone”, oxytocin is released in response to a variety of environmental stimuli including skin-to-skin contact and cervical stimulation experienced during sex. At normal levels oxytocin encourages a mild desire to be kissed and cuddled by partners. Being touched (anywhere on the body) leads to a rise in oxytocin levels. This causes a cascade of reactions within the body, including the release of endorphins which results in both biological and psychological arousal.42
Growth hormone replacement therapy (GHRT) is a regimen for treating deficiencies in children and adults whose bodies, for one or more reasons fail to produce adequate somatropin (somatotropin, human growth hormone, hGH). This hormonal deficit contributes to poor growth and development in children, and in adults fails to maintain essential aspects of bodily form and function that are needed for a healthy life of normal duration.
The medical condition resulting from inadequate production and/or utilization of hGH is called growth hormone deficiency (GHD).43 Most cases are initially observed as an endocrine disorder in children that occurs equally in males and females, although males are often diagnosed more frequently.4445 Because of its significant effect on growth and development as well as causing associated medical problems and reduced quality of life, childhood-onset GHD has been treated with replacement therapy for more than 30 years. In the past, hGH therapy in children affected by GHD was stopped at the time of epiphyseal closure (i.e. at final height). This focus on height originally reflected a measure of successful GH replacement therapy (GHRT) after which treatment was ended. This was done, in part because hGH was originally extracted from human cadavers making its supply fairly limited. However, with advances in technology it became possible to clone the gene capable of producing hGH. Thereafter, the recombinant form of human growth hormone (rhGH) became available in unlimited quantities. Because of its availability for clinical application, rhGH became and is now the drug of choice, not only because of its efficacy, but also because it avoids the risk of transmitting fatal, slow viral (prion-mediated) Creuzfeldt Jacob Disease which was sometimes associated with the cadaver-derived hormone.46 Although originally indicated for use in childhood GHD, rhGH became a licensed indication for GH-deficient adults in the United States, a number of European countries, and New Zealand in 1996. This action was taken because people who had been treated with rhGH as children and then routinely discontinued from treatment upon reaching final height, experienced higher than expected rates of medical problems as adults, beginning in their 30s and 40s. These included reduced physical, mental, and social energy, excess adipose tissue, diminished muscle mass, diminished libido, poor bone density, higher than normal cholesterol levels, and elevated rates of cardiovascular disease. Research trials soon confirmed that a few months of GH replacement therapy could improve nearly all of these parameters in GHD patients. Coincidentally, it was noticed that the same intrinsic diseases as well as maladaptive changes in form and function also occur spontaneously with advancing age.47
The progressive age-associated decrements in function of the GH neuroendocrine axis are collectively referred to as the somatopause. The term represents cessation of optimal secretion of somatotropin (hGH) which is analogous to declining production of reproductive hormones during the menopause and andropause in women and men, respectively. However, there are pathophysiological differences in childhood-onset and adult-onset GHD (AGHD) when compared with progressive, age-related GHD. Initial investigations into the causes of adult onset GHD showed them to result from damage to the pituitary gland due to tumors, surgery or radiotherapy that disrupted function of the GH neuroendocrine axis.4849 Since age-related GHD is not associated with the strict and exclusive acceptance of these originally defined, causal criteria for adult-onset GHD, nor is aging generally considered a “disease”, there was and continues to be reticence to diagnose GHD in the obese and in the elderly.505152 Thus at first, little attention was paid to the fact that as the body ages, progressive dysfunction of the GH neuroendocrine system results in clinical symptoms similar to those associated with factors originally recognized as causal for GHD.
For these reasons, administration of rhGH which is the accepted treatment for GHD, has not been permitted for use in aging by regulatory guidelines promulgated by the FDA. As a result, rhGH supplementation is not approved for medical treatment of the pathophysiologic, age-related decline in GH/IGF secretion, despite the clinical similarities with classically defined, adult-onset GHD. If used at all, lower doses are recommended in the elderly to reduce the incidence of side effects and maintain age-dependent normal levels of IGF-1. This is a confusing recommendation for the following reason. IGF-1 levels in normal young adults is higher than those in GHD adults. However, serum IGF-1 values in both groups are indistinguishable by the age of 40. Nonetheless, the declining values in “normal” aging people are not considered to be diagnostic criteria for GHD or GH insufficiency worthy of treatment with rhGH. Instead the range of laboratory reference values are shifted downward to reflect those in human subjects as they advance in age. Surprisingly, this is a unique practice which is not done for serum values of any other hormones. Nonetheless, it restricts in part, diagnosis of idiopathic GHD and treatment with rhGH to those under 40, and thereby requires different treatments for medical issues related to age-associated, GH insufficiency. To differentiate between classically defined adult-onset and age-related GHD associated with the somatopause, the latter is often called growth hormone insufficiency (GHI). Thus, because of the similarities between GHD resulting from trauma, disease or radiation from effects of aging that occur during middle and later stages of life, endocrine therapies for treating the latter condition have been sought over the past two decades.53 In fact many years of off-label use of sermorelin, a GH secretagogue, has improved the life and health of many suffering from progressively degenerative conditions of aging.
Many of the body’s systems that function to maintain optimal health and well-being decline with advancing age. Aerobic capacity, muscle mass, and strength all progressively decline with age. Loss of muscle mass, or sarcopenia, and the accompanying reduction in strength increases the risk of falls and their complications, and for many individuals the associated loss of physical, functional capacity leads to increasing difficulty in living independently. Complaints of poor sleep are common in older populations. Insomnia reduces quality of life and is often a factor in decisions to seek health care. Sleep complaints often lead to overmedication and sedation of the elderly, with the numerous potential attendant problems, including increased morbidity and mortality. Finally, cognition also declines with advancing age, particularly those cognitive functions that involve novel problem solving and psychomotor processing speed, with its own related impact on the older individual’s ability to function independently.54 Aging in both sexes is accompanied by profound decreases in GH output and in plasma IGF-I concentrations. This effect is separate from the alterations in body mass index that accompany the normal aging process. Attenuation of GH output associated with aging is related by inference to reduced GH-releasing hormone (GHRH) production, pulse amplitude as well as increased somatostatin (SRIF).555657
GH secretion rates decline exponentially from a peak of about 150 μg/kg/day during puberty to about 25 μg/kg/day by age 55.56 During this process there is a reduction in GH pulse amplitude, but little change in GH pulse frequency.58 There is a particularly marked decline in sleep-related GH secretion, resulting in loss of the nocturnal pulsatile GH secretion seen in younger individuals and lack of a clear night-day GH rhythm.5960 The decline in GH production parallels the age-related decline in body mass index and is associated with alterations in body composition, hormonal status, and functional capacity that mimic the changes seen in AGHD or partial hypogonadism.61 In addition to deteriorating memory and cognitive function, the changes in body composition that are most pronounced in normal aging include a reduction in bone density and in muscle mass and strength, an increase in body fat, and adverse changes in lipoprotein profiles.6263 While the aging pituitary remains responsive to GH, GHRH, and GH secretagogues, it is less responsive to stimuli such as exercise. This decline in GH production is initially clinically silent, but may contribute over time to sarcopenia and frailty. Since GH secretion declines progressively and markedly with aging, and many age-related changes resemble those of partial adult-onset GHD, stimulating production and secretion of endogenous GH with GH-releasing hormone (GHRH) or its analog Sermorelin, a GH secretagogue, could confer benefits in normal aging similar to those observed in AGHD. In particular, such treatment could reduce the loss of muscle mass, strength, and exercise capacity that leads to frailty; thereby prolonging the ability to live independently.
Growth Hormone Secretagogues
Growth hormone secretagogues (GSH) are a class of molecules that stimulate the secretion of GH from the pituitary gland. They include agonists of the hypothalamic and pituitary ghrelin receptors (GHRPs, ipamorelin, hexarelin, etc.), and those of the pituitary GHRH receptor such as Sermorelin.
Sermorelin is a synthetic (man-made) version of naturally occurring GHRH that is produced in the brain and can be used clinically to stimulate release of growth hormone (GH) from the pituitary gland.64 Growth hormone is necessary for growth in children and is important in adults to maintain metabolic and physiologic functions that are necessary for good health and quality of life. Thus, Sermorelin can be effective in cases of GH insufficiency and thereby sustain essential bodily functions throughout life.
Some uses for Sermorelin include: Diagnosis of growth hormone deficiency/insufficiency (GHD),65 treatment of children with idiopathic growth hormone deficiency,66 management of adult-onset growth hormone deficiency/insufficiency and other conditions requiring GH replacement therapy (GHRT),6767 regeneration of pituitary function and delay its functional decline during aging6668
After Roger Guillemin and Andrew Schally were awarded the 1977 Nobel Prize in Medicine for their work on neuroendocrine releasing factors, the precise chemical structure of GHRH, a 44 amino acid peptide, was determined using tissue from human pancreatic tumors that caused acromegaly, a disease resulting from excess secretion of GH.69 The following year, Wehrenberg and Ling70 sought to determine which part of the molecule was essential for its pituitary stimulating action. By eliminating individual amino acids and then testing the remaining peptide fragments, they found that only the first 29 amino acids are needed for stimulating pituitary production and secretion of HGH. Consequently, this fragment of the native molecule, commonly known as Sermorelin is often used to treat GH deficient states in children and adults
Chemically, sermorelin is known as growth hormone releasing factor (GRF) or growth hormone releasing hormone (GRH)1-29 NH2 indicating that the amino terminus is at position 29. However, the molecule is not used clinically as the free base, but rather as the acetic acid salt, i.e. as sermorelin acetate. The free base of sermorelin has the empirical formula C149H246N44O42S and a molecular weight of 3,358 daltons71 Sermorelin acetate is a sterile, non-pyrogenic, lyophilized powder intended for subcutaneous injection after reconstitution with Bacteriostatic Water for Injection and should be stored at between 36 and 46° F (2 and 8° C). Taxonomically, sermorelin is listed as an organic compound (kingdom), an organic acid (superclass), a carboxylic acid (class), amino acid/peptide analogue (subclass), and as a peptide (direct parent).72
Sermorelin is the most widely used member of the GHRH analogue drug class. It can significantly promote the synthesis and release of growth hormone (GH) from cells in the pituitary gland, improving the serum concentrations of GH and subsequently insulin-like growth factor 1 (IGF-1) in animals and humans.7374 It is able to influence the concert of hormonal signals that affect GH secretion from the anterior pituitary including GHRH, somatostatin, and insulin like growth factor (IGF) and others. The positive and negative opposing regulation of growth hormone by GHRH and somatostatin, respectively, creates a rhythmic-circadian pattern of GH secretion.75 Thus, modification of both pulse amplitude and frequency of GH secretion results from Sermorelin administration.76 After sermorelin stimulates the release of GH from the pituitary gland, it increases synthesis of IGF-1 in the liver and peripheral tissues.76
Sermorelin acts on the growth hormone releasing hormone receptor (GHRHr) in the pituitary to regulate cellular activities. GHRHr is the natural receptor for the endogenous hormone, GHRH, and for sermorelin. This receptor regulates growth hormone release directly by stimulation and indirectly by a feedback relationships with somatostatin.77
Sermorelin is readily degraded after reaching the bloodstream, having a biological half-life of approximately 10-20 min.78 Due to the biological half-life and bioavailability of Sermorelin, administration for growth in childhood GHD must occur periodically several times a day as subcutaneous-injections.79 However, single daily dosing is sufficient to treat most cases of adult-onset GH insufficiency. Three (3) mcg/kg subcutaneous-injections of Sermorelin have been reported to simulate a naturally occurring GHRH mediated GH release responses.80
In addition to increasing production and secretion GHRH also affects sleep patterns by increasing the amount of slow wave sleep (SWS) while augmenting sleep-related GH secretion and reducing cortisol secretion.81
To exert all its beneficial effects, Sermorelin requires a functioning pituitary and a host of peripheral tissues.8283 This is due to the reliance on endogenous receptors controlling hormone secreting glands and tissues. More precisely, functioning growth hormone releasing hormone receptors (GHRHr) are required on somatotrophs in a functioning anterior pituitary.82
Because of Sermorelin's ability to bind receptors on somatotrophs, the pituitary cells that produce and secrete GH, sermorelin has several clinical indications and applications related to GHRH/GH insufficiency.84 For example it is officially indicated and approved for diagnostic evaluation of pituitary function and also for treatment of delayed or inadequate growth in children. It also can be used to oppose maladaptive changes in body composition such as reduced lean body mass (muscle), increased total and visceral fat, and decreased bone mass resulting from low or inadequate concentrations of serum GH and insulin-like growth factor-1 (IGF-1).
Data from research and clinical studies have demonstrated sermorelin’s multifaceted properties, some of which include:
- Peak increases in hGH followed administration of GHRH analogs after 15 or 30 min. An increase in the integrated plasma growth hormone (GH) response was observed at each dose.85
- Quality of life parameters including general well-being (P < 0.05) and libido (P < 0.01) significantly improved in men receiving sermorelin therapy.86
- Youthful concentrations and patterns of serum hGH were restored in older persons by daily injections of GRF (sermorelin).87
- Body composition improved after regular administration of GRF for 90 days resulting in increased muscle mass, increased total body water and decreased visceral fat.88
- Quality of sleep improved as indicated by extended Stage IV and Slow Wave Sleep in men.89
Symptoms and Diagnosis of Adult Growth Hormone Deficiency
Adults with inadequate concentrations of serum GH can have a variety of signs and symptoms, some of which include abnormal body composition, reduced fluid volume, diminished strength, physical energy and stamina, lack of motivation, lethargy, lability etc. Symptoms of growth hormone deficiency also depend on age, and often those meeting the classic definition of adult onset GHD can have different symptoms than a child similarly diagnosed. However, those with adult-onset GHD that are causally unrelated to aging have similar clinical symptoms as those that occur progressively in incidence and severity with advancing age.90
Not everyone with growth hormone deficiency/insufficiency will have the same symptoms. Some people will only have one or two while others can have multiple symptoms. Fortunately, certain tests and exams can help physicians to make an appropriate diagnosis. Exams and tests used to diagnose growth hormone deficiency are the same no matter the patient’s age.
Diagnosing growth hormone deficiency typically starts with a physical exam. The physician checks weight, height, and body proportions. Other than a physical exam, there are many other tests and exams used to make a growth hormone deficiency diagnosis.
With respect to diagnosis of adult GHD of classical etiology, guidelines state that “adult patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, head trauma, or evidence of other pituitary hormone deficiencies are considered appropriate for acquired GHD” and that “idiopathic GHD as which occurs during aging requires stringent criteria to make the diagnosis. The reason for this restriction is that as previously described, the age-related decline in function of the GH neuroendocrine axis is accepted as being a “normal” part of aging, even though it is progressively detrimental to many aspects of body function. Thus, due to the nature of the original diagnostic criteria for GHD, and the reticence to consider aging a “disease” per se, even though disease risk, incidence and severity can be attributed at least in part to declining activity of the GH neuroendcrine axis, the criteria for determining if secretagogue therapy is indicated as an intervention in aging, are less stringent than those promulgated by Endocrine Society guidelines.53
Some or all of the following tests can be used to diagnose age related GH insufficiency, since everyone will be so affected over the course of their lives. Such diagnostic testing may be used to determine the degree to which replacement therapy is indicated, i.e., for dosing determinations. Tests include:
Blood Tests for Growth Hormone Deficiency
- Binding protein level (IGF-I and IGFBP-3) blood tests to determine whether or not the problem is caused by the pituitary gland
- Blood tests to measure the amount of growth hormone levels in the blood
- Blood tests to measure other levels of hormones the pituitary gland produces
- GHRH (Sermorelin)-arginine provocative test
- Other GH provocative stimulation tests
- Insulin tolerance test
Other Exams/Tests to Diagnose Age-unrelated Severe Growth Hormone Deficiency
In addition to blood tests, a physician may perform some additional exams and tests to help diagnose growth hormone deficiency. These may include:
- Dual-energy x-ray absorptiometry (DXA) scan to measure bone density.
- Brain MRI to examine the pituitary gland and hypothalamus.
- Hand x-rays (typically of the left hand) to examine the shape and size of bones which change as a person grows and ages. Bone abnormalities can be observed with x-ray examination.
- X-rays of the head can show any problems with the bone growth.
If an individual experiences signs and symptoms of GHD or GHI, he/she should talk to a doctor immediately so as to perform exams and tests that assist in making an accurate endocrine analysis and diagnosis.
Treatment of Growth Hormone Deficiency
While aging is not a disease, it results in significantly maladaptive changes in body composition and function which affect the individual and the community at large. While aging is associated with a milder form of adult GHD, GH replacement with secretagogues such as Sermorelin has met with success. Once daily injections can stimulate increases in GH and IGF-I at least to the lower part of the young adult normal range.91 Because peptides like Sermorelin are readily destroyed by enzymes in the digestive tract, subcutaneous (sc) or intravenous (iv) injections are the only way to administer the molecule. Since iv injections are impractical for most people, the sc route is commonly used to administer doses of Sermorelin ranging between 0.2 – 1.0 mg per day. The most commonly used dosage is 0.5 mg daily. In a University of Washington study consisting of 6 months treatment with daily bedtime subcutaneous injections of Sermorelin, alone or in combination with supervised exercise conditioning, IGF-I levels rose approximately 35%. As with GH, subjects showed an increase in lean body mass and a decrease in body fat (particularly abdominal visceral fat).9293 Such changes indicate that regular GHRT with Sermorelin can resist changes in body composition underlying sarcopenia and frailty that lead to loss of independence. Thus, since the aging pituitary remains responsive to GH and GHS, it is reasonable that stimulation with Sermorelin is indicated in aging.94 While elders are more sensitive to GH, and thus more susceptible to the side effects of replacement with rhGH, stimulating production and secretion of endogenous GH with Sermorelin offers the advantage of a more physiological approach to increasing GH pulsatility while reducing risk for side effects.
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