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.
What Are Hormones
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
Functions of HRT
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).
How Hormone Replacement Works
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.
Types of Hormone Replacement Therapy
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
Restoring Hormonal Balance
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.
Mass-Produced HRT Formulations Are Useful But Limited
There are many mass-produced hormone treatments on the market today. However, every woman's body, and her individual hormonal makeup, is different and each requiring a unique balance of hormones. That's why more women are turning to custom compounded HRT from Empower Pharmacy for their hormone replacement needs. We specialize in preparing a variety of custom supplements, and we can compound a customized HRT solution to suit your very specific hormone needs.
Working with both you and your physician, your Empower Pharmacy compounding pharmacist will assist in evaluating your serum or saliva tests and hormone evaluation worksheet. By studying and interpreting your results, your care team will determine an individualized course of treatment for you. Then, with your healthcare provider's prescription, we can prepare hormones in a variety of strengths and preparations including:
- Sublingual drops or troches
- Gels and foams
- Topical or vaginal creams
Hypothyroidism is a state in which the thyroid gland does not produce enough of the two thyroid hormones. Although the people with the highest risk are women over 60,20 it can occur in people of all ages. Damage to the thyroid gland as a result from viral infections, drugs such as lithium, or radiation therapy for cancer, genetic predisposition, or an idiopathic source can all result in hypothyroidism.21 Symptoms of hypothyroidism may include:22
- Unexplained weight gain, puffy face, dry skin
- Elevated blood cholesterol level, slowed heart rate
- Pain, stiffness or swelling in your joints, muscle aches, fatigue
- Heavier than normal or irregular menstrual periods
- Thinning hair, hoarseness, constipation
- Depression, Impaired memory
Thyroid hormone exists in two major forms: the prohormone (precursor) thyroxine (T4), an inactive form with a 4th iodine that is produced exclusively by the thyroid gland, and triiodothyronine (T3), the active form of thyroid hormone created by removing a specific iodine atom from T4.23 About 20 percent of T3 is produced by the thyroid gland, with the remaining majority of T4 produced in various tissues of the body when and where more T3 is needed.24
The active form of thyroid hormone (T3) helps control heart rate and blood pressure and therefore a thyroid hormone imbalance has a profound effect on cardiovascular fitness.2526 When T3 levels drop, the liver no longer functions properly and produces excess cholesterol, fatty acids, and triglycerides, which increase the risk of heart disease.27 Additionally, hypothyroidism is the second leading cause of high cholesterol, after diet.28 High cholesterol may also increase the risk of Alzheimer's disease29 alarmingly severe hypothyroidism can even produce symptoms similar to those of Alzheimer's disease as well30 and T3 is further important in the production of neurotransmitters and myelin, thusly it is critical to the health of the mind as a whole.31 With such a far-reaching sphere of influence, it isn’t surprising to see that thyroid function is of great concern to medical professionals and when a person begins showcasing symptoms of hypothyroidism, doctors immediately turn to pharmaceutical solutions.
The four classes of thyroid medication offered by Empower encompass the complete spectrum of treatment options available and are designed to meet each patient’s specific needs: Thyroid USP, isolated from natural porcine thyroid,32 offers patients both T4 and T3; levothyroxine sodium, the most commonly prescribed thyroid medication globally,33 is synthetic T4 in a stable sodium salt form; liothyronine, and custom combinations for combination therapy sodium, synthetic T3 in the same stable sodium salt form.34 Additionally, Empower is able to help physicians develop personalized formulations for combination therapy.
Currently, Desiccated Natural Thyroid - Thyroid USP - is available in all strengths only through compounding pharmacies. The specifications for Thyroid USP powder require that each grain contains 34.2-41.8 mcg levothyroxine (T4) and 8.1-9.9 mcg liothyronine (T3) in order to produce a T4:T3 ratio of 4.22:1 to meet the stringent standards of the U.S. Pharmacopeia monograph,35 with a permissible variance of ± 10%.35 Armour Thyroid, WesThroid, and Nature-Throid, some of the most widely used brand-name versions of desiccated thyroid, also adhere to these guidelines. However, the different brands of Thyroid USP contain other ingredients than just desiccated thyroid:363738 fillers, dyes, binders, stabilizers, excipients, many of these compounds can be a concern for patients with allergies. These additional compounds carry the potential to affect the properties of the drug itself as the public outcry over the purported 2009 reformulation of Armour Thyroid so clearly demonstrates.39 This is why Empower Pharmacy’s formulation is a gelatin capsule containing desiccated thyroid, a natural cellulose filler and nothing more.
Through a very meticulous process, compounding specialists at Empower Pharmacy use this raw thyroid powder to compound Thyroid USP. If you are already on Thyroid USP but have a unique dose, Empower's custom preparations could mean it's no longer necessary to split your Thyroid USP tablets—we create customized doses not commercially available. In addition, if you have side effects due to the inactive ingredients of the Armour Thyroid, WesThroid, or Nature-Throid brands, we can compound the strength you need with minimal fillers. By prescription, we can compound Thyroid USP in the doses that your patients need, and can omit problem-causing fillers and excipients that are found in the commercial product but may not be tolerated by all patients.
Levothyroxine Sodium (T4)
However, due to the difference between pig and human T4 to T3 ratios (4.22:1 in pigs and 14~20:1 in humans)40 as well as considerable variation in levothyroxine (T4) and liothyronine (T3) [levels], porcine thyroid hormone has been largely replaced in clinical pharmacological therapeutics by synthetic levothyroxine (T4), which has a more reliable hormonal content.”41
Levothyroxine Sodium (T4), the most widely used form of treatment for hypothyroidism, helps elevate T3 levels by introducing additional amounts of T4 into the body so that more T3 can be created in the tissues of the body that need it.42 The rationale behind using levothyroxine sodium (T4) alone (monotherapy) is that the thyroid only makes 20% of the body’s T3—the other 80% is made from T4 elsewhere in the tissues of the body21 so by bringing up a patient’s T4, T3 ought be more readily made throughout the body. Levothyroxine sodium relies on the conversion of T4 to T3 to combat the deficiency of both thyroid hormones throughout the body: only by successfully and sufficiently converting T4 to T3 does the body reap the full benefits of levothyroxine sodium. Fortunately, a demanding majority of the hypothyroidic population is able to do just that43 which is why levothyroxine sodium is the most widely prescribed drug for hypothyroidism and the fourth most prescribed drug in the world.44
On the other hand, some people prefer taking both synthetic T3 and T445 while others who aren’t able to convert enough T4 to T3 in the body essentially require T3 in their medication which is why Empower provides physicians with all the components along the continuum of thyroid treatment options: desiccated thyroid (T4 & T3), levothyroxine sodium (T4), and lastly liothyronine sodium (T3); a T3 deficiency cannot be fully treated if the rate at which T4 is converted to T3 is hindered.
Synthetic T3 (liothyronine) is commercially available only as an immediate-acting preparation, which may cause undesirable side effects including heart palpitations46 in the recommended dose of 5-50 mcg.47 This is why some practitioners choose to use lower doses of T3 or provide T3 as a sustained release preparation, both of which are available from our compounding pharmacy.
While liothyronine sodium is not typically employed by itself to combat hypothyroidism,48 some people still find it works best for them. Interestingly, the most prominent use of T3 on its own (monotherapy) is in combating certain forms of depression due to the effect T3 indirectly exerts on serotonin levels,49 Liothyronine is not, though, typically employed by itself to combat hypothyroidism.48 However, there are proponents in the medical community who believe that T3 monotherapy can provide certain patients relief from their symptoms they were unable to attain with Thyroid USP or levothyroxine previously.50 on the whole, liothyronine sodium is far more frequently utilized in combination with levothyroxine sodium in what’s known as “combination therapy”.
The Case for Combination Therapy
Several studies have shown the possible superiority of combination therapy (Liothyronine sodium with levothyroxine sodium)5152 while others have found no difference.53 This inconsistency in the medical literature, as well as the possible side effects of combination therapy like palpitations54 have led some experts to conclude that there is no benefit to using T3 for treating hypothyroidism.55
Yet where these studies don’t offer an indisputable rationale either for or against T3/T4 combination therapy, the very genes of 15% of the hyporthyroidic population provide a compelling justification: while 85% of the population is able to successfully increase T4 and T3 levels when treated with levothyroxine sodium (T4) alone, the other 15% doesn’t see enough of an increase in their levels of T3 even though T4 levels are increased.56 This happens because that 15% has a different form (polymorphism) of the gene DIO2 (14q24.2-q24.3)57 this gene is not expressed as much or as easily as it is in the rest of the population and as a result the enzyme it creates, type 2 deiodinase (IDII), one of the two enzymes that convert T4 into T3,58 is not as prevalent making a person in this 15% of the population less able to turn T4, even when supplemented, into a sufficient supply of T3 throughout the body. Without enough functioning IDII more T4 will become rT3 than is normal, which can further decrease thyroid function.
The gene DIO2 is a fantastic case-study in why treating all cases of hypothyroidism with the same conventional methodology might not be the most prudent approach, nor might it yield the best results—these are two populations that react very differently to typical levothyroxine sodium treatment: while one group achieves the desired T3 levels, the other does not. For these individuals, levothyroxine sodium (T4) alone is incapable of fully remedying the symptoms of hypothyroidism: these people cannot convert their new, large stores of T4 into T359 (and having too much T4 without enough IDII can even make the problem worse—T4 that that doesn’t become T3 is more likely to become reverse T3 which decreases the thyroid’s function as a whole).59 T3 is, in theory and in practice, tantamount to essential for these individuals.
Custom Thyroid Solutions
As is the usual in medicine, the answer to “what thyroid medication is best for me?” is not be a simple one, nor should it be: Thyroid USP, Levothyroxine, Liothyronine, and combinations in concert all carry a unique profile of advantages, disadvantages, and nuance. 75% of all medicated hypothyroidics still experience at least one symptom to varying extent60 and it is absolutely imperative that healthcare providers have every resource and every tool at their disposal if a patient is to achieve an optimal quality of life.
This is why Empower offers you/your patient as potent a tool-kit possible: Thyroid USP, Levothyroxine, Liothyronine—with complete control over dose composition and strength, binder, filler, and excipient alternatives, and the ability to decide whether or not to utilize instant- or extended-release.
While it has been demonstrated that some people can experience unpleasant or sub-optimal results from combination therapy,61 there are also those who experience both qualitative62 and quantitative benefits/symptom relief.63 Everyone’s solution is unique, and considering that roughly 75% of all medicated hypothyroidics still experience at least one symptom of their disease to an extent,64 it follows that the treatment practices proclaimed as the universal gold standard in the past (levothyroxine sodium monotherapy)65 might not be those that ought be exclusively used in the future.
Parting Considerations: the Industry, Dosing, and Nuance
Non-compounded medication, referred to elsewhere in this article as commercially available drugs, possess many properties that Empower emulates—these products are approved by the FDA for a reason, and their rigid profiles are designed to allow for standardized treatment physicians across the world can easily apply.66
It is crucial to remember this: the purpose of custom combination therapy & personalized compounding solutions is not meant to replace and certainly not to declare superiority over the conventional treatments offered by the pharmaceutical industry. Compounded medication is meant to offer physicians and patients alike every possible choice in combatting disorders that are, by the very nature of physiology, unique to each person. In some people, traditional methods like levothyroxine sodium work just fine. In others the persistence of symptoms, even if they’re markedly improved from before treatment, implies that traditional methods leave something to be desired. With hypothyroidism, this is roughly 75% of the population64 75% of people may stand to gain from pharmacological solutions that go beyond convention, that consider and combat all of the possible nuances in treatment the disease might present.
In the case of hypothyroidism, a frequently overlooked nuance that many physicians find provides a readily accessible improvement in treatment is considering whether instant or extended release works better for a patient. Most all commercially mass-produced thyroid drugs only offer one or the other and in almost every case an instant release preparation (see: package inserts for the mass-produced products for each of the 3 classes discussed in this article).
Empower offers physicians & patients a choice in the matter, especially in light of a substantial body of evidence that asserts extended-release versions of Thyroid USP, levothyroxine sodium, and liothyronine sodium can provide some people superior results and an improved quality of life.6768
Empower has the ability to compound Thyroid USP, T3 (liothyronine) and/or T4 (levothyroxine) alone or in customized combinations. These are also available in Immediate Release and Sustained Release preparations.
Human chorionic gonadotropin (HCG) is used as a hormonal therapy to utilize the effects of pituitary derived endogenous gonadotropins, including luteinizing hormone (LH) and follicle stimulating hormone (FSH).
HCG is a glycoprotein composed of 237 amino acids.69 HCG is similar in structure and function to LH, and is thus prescribed by many physicians to mimic many of the physiological effects of LH. The reason that HCG is prescribed over LH is due to HCG’s more stable nature, greater physiological activity and longer circulating half-life. HCG has a half-life in the range of hours while LH has a half-life in the range of minutes. The half-life of LH is physiologically important and allows for a pulsatile LH systemic exposure. HCG’s half-life and higher binding affinity for the mutual receptor ultimately allows it to be more biologically active than LH.7071
LH and HCG are widely regarded as analogous hormones due to the similarity in the structure of the hormones, including the similar alpha subunits which exhibit similar biologic activities when associated with the beta subunit.72 Furthermore, the HCG alpha subunit is identical to that of LH, FSH and thyroid-stimulating hormone (TSH). The beta subunit is unique to HCG.
LH and HCG share a mutual receptor, however events after receptor binding are different between the two hormones.73
History of HCG
Human chorionic gonadotropin (HCG) and a recombinant formulation, called choriogonadotropin alfa (r-HCG), is a gonad-stimulating polypeptide hormone normally secreted by the placenta during pregnancy. The non-recombinant products are obtained from the urine of pregnant women. Recombinant-HCG is produced via recombinant DNA techniques in Chinese Hamster Ovary (CHO) cells. The pharmacological actions of HCG and of r-HCG are similar and resemble those of luteinizing hormone (LH); HCG is generally used as a substitute for LH.
HCG has been used to treat cryptorchidism or hypogonadotropic hypogonadism in males, sometimes in combination with menotropins or follitropin. Interestingly, HCG was introduced for the treatment of cryptorchidism in 1931, and remained the only hormonal agent available to treat the condition until the 1970's, when gonadotropin-releasing hormone (GnRH) analogs also became a treatment option.
Urine-derived HCG was first approved by the FDA in 1939, and received subsequent approval for additional indications in 1973. Ovidrel®, the first recombinant HCG (r-HCG), received FDA approval for female infertility to induce final follicular maturation on September 20, 2000. Ovidrel® pre-filled syringes received FDA approval in October 2003; manufacturing of Ovidrel® vials has ceased.
HCG in Testosterone Replacement Therapy
HCG binds to receptors that are present in reproductive tissues in the male, regulating fertility. HCG is increasingly used in combination with Testosterone Therapy. When exogenous Testosterone is administered it influences the balance of the hypothalamus – pituitary – gonadal (HPG) axis. Due to the testosterone’s aromatization into estrogenic metabolites and direct androgenic effects, endogenous testosterone production is down regulated.
Estrogenic and androgenic mediated negative-feedback reduces the secretion and activity of gonadotropin releasing hormone (GnRH) and therefore reduces gonadotropin secretion. Gonadotropins control the functionality of the gonads, including their production of hormones and physiological processes. More specifically, the reduction in LH and FSH activity reduce testicular spermatogenesis and testicular produced testosterone. Testicular atrophy is resultant of insufficient gonadotropin signaling. HCG is commonly used during and after testosterone therapy to maintain and restore testicular size, endogenous testosterone production and spermatogenesis.
HCG administration acts as supplemental gonadotropin, replacing absent LH activity. HCG stimulates the Leydig cells to synthesize intratesticular testosterone, this testosterone is essential for spermatogenesis occurring in the Sertoli cells.
During testosterone therapy HCG has been found to maintain the level of intratesticular testosterone, and maintain normal spermatogenesis. To achieve this effect 500 IUs of HCG were administered every other day during testosterone therapy.7475
HCG in Hypogonadotrophic Hypogonadism
In idiopathic hypogonadotrophic hypogonadism patients, ranging in age from 12 to 24, HCG (1,500-2,000 IU) was administrated intramuscularly, 3 times per week, for 8 weeks. The HCG treatment increased the serum testosterone level, penile length, and testicular volume in idiopathic hypogonadotrophic hypogonadism patients.76 An increase in Penile length by HCG treatment has been shown.76
HCG Regulation of Hypothalamus – Pituitary – Gonad Axis (HPG) in Males77
Tissues Involved in the Male HPG Axis
- Hypothalamus- produces Gonadotropin-releasing hormone (GnRH).
- Pituitary- produces gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
- Testes- contains Leydig cells and Sertoli cells. Produces testosterone which is metabolized into a cascade of metabolites most importantly including estrogen and progesterone. Facilitates spermatogenesis.
Hormones involved in the HPG axis
- Gonadotropin-releasing hormone (GnRH)- signals the pituitary to release FSH and LH in a pulsatile fashion.
- Luteinizing Hormone (LH)- binds with receptors on Leydig cells and interstitial cells in the testis, and promote the secretion of androgens by the Leydig cells.
- Follicle-Stimulating Hormone (FSH)- binds with Sertoli cells which build the microenvironment of spermatogenesis, regulates the maturation of spermcells.
- Estrogen- estrogen receptors in the hypothalamus and these receptors direct the negative feedback of GnRH secretion, negatively regulate at a pituitary level and gonadal cell level in an autocrine manner.
- Androgens- androgen receptors in the hypothalamus direct the negative feedback of GnRH secretion, regulate hormonal synthesis at gonadal cell level in an autocrine manner. Androgens have strong suppressive effects on gonadotropin synthesis in the anterior pituitary.
- Progesterone- negatively regulates the organizing hormone synthesis.
- HCG- mimics the functions of LH.
HCG Mechanism of Action
The mechanism of action of human chorionic gonadotropin (HCG) depends upon the purpose for which it is being used, the sex of the patient, and the level of maturity of the patient to whom it is administered.
Adult and adolescent males: In adult and adolescent men with hypogonadotropic hypogonadism, HCG acts like LH and stimulates testosterone production in the Leydig cells and spermatogenesis in the seminiferous tubules. Stimulation of androgen production by HCG causes development of secondary sex characteristics in males (e.g., deepening of voice, facial hair, etc.). Human chorionic gonadotropin (HCG) also stimulates the Leydig cells to produce estrogens; increased estrogen levels may produce gynecomastia in some males. Once HCG is initiated, it takes at least 70—80 days for germ cells to reach the spermatozoal stage. Response to treatment is also noted by the development of masculine features and the normalization of serum testosterone levels. Induction of testicular growth and increased sperm volumes may help to restore fertility in these men after many months to years of treatment, which is then sometimes combined with the use of either menotropins or follitropin.
Adult females: In select females with infertility , human chorionic gonadotropin has actions essentially identical to those of luteinizing hormone (LH). Human chorionic gonadotropin (HCG) also appears to have additional, though minimal, follicle-stimulating hormone (FSH) activity. By administering HCG after follitropin, menotropins, or clomiphene, the normal LH surge that precedes ovulation can be mimicked. Human chorionic gonadotropin (HCG) promotes the development and maintenance of the corpus lutetium and the production of progesterone. Following HCG administration, final luteinization or maturation of the oocytes occurs and either ovulation can ensue for timed insemination techniques, or oocyte retrieval can take place for assisted reproductive technology (ART) procedures such as in vitro fertilization (IVF). Once pregnancy takes place, endogenous HCG is normally secreted by the placenta to support the continued secretion of female hormones and the corpus luteum.
Male infants and children: In the male infant, normal testicular descent is complete by 3 months of age. Testicular descent occurs secondary to an endogenous testosterone surge stimulated by pituitary gonadotropins in response to the discontinued exposure to maternal circulating estrogens upon birth; this testosterone surge peaks within 60 days postnatally. In male infants and children with cryptorchidism, HCG acts like LH and causes the Leydig cells of the testes to produce a testosterone surge and induce the descent of palpable testes. The hormonal stimulation by HCG may result in an early pseudopuberty, and in some cases, the response to hormonal therapy may be temporary in 10—20% of cases. Hormonal therapies like HCG have not replaced the primary surgical treatment for the condition, which is orchiopexy within the first 1—2 years of life. Early animal studies have suggested that HCG may be used as an adjunct to orchiopexy to help preserve fertility, but human data is lacking.
Activity on body composition (all sexes): Human chorionic gonadotropin has no known effects on appetite, or on mobilization or distribution of body fat. It is not an effective treatment for obesity. In sport, athletes use HCG as an 'undetectable' anabolic steroid; HCG increases the body's production of testosterone and epitestosterone without increasing the ratio of the two hormones in the urine above normal values. Urinary testing is being developed which should allow for discriminate testing of HCG doping in sport.
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.78 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.79 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.80 Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behavior.81
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.82
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.83
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.84 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.85 Oxytocin nasal spray has been used successfully to help treat for "the let-down effect".86 There is speculation that in addition to facilitating lactation and the birthing process, the hormone facilitates the emotional bond between mother and child.87
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.88899091929394
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.9596
Oxytocin has also become the subject of studies in female sexual dysfunction specifically difficulty achieving orgasm. Oxytocin increases sexual receptivity and counteracts impotence.97 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.98
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.99
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.100
Sermorelin acetate is a synthetic analog of naturally occurring Growth Hormone-Releasing Hormone (GHRH). GHRH is produced in an area of the brain called the hypothalamus from which it is released into blood vessels that carry it to the pituitary gland. Once there, it stimulates production and secretion of growth hormone (GH) which is necessary for growth and development during childhood, as well as for maintenance of normal body composition and metabolism in adults. When GH concentrations are low, deficiency causes poor growth, inadequate muscle and bone development, as well as increased risk for development of intrinsic diseases such as diabetes and other pathologies. Such deficiencies can be opposed by administration of sermorelin which stimulates the pituitary gland to increase output of GH and thereby elevate and restore its serum concentrations to normal levels.
Growth Hormone Replacement
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).101 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.102103 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.104 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.105
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.106107 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.108109110 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.111 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.112 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).113114115
GH secretion rates decline exponentially from a peak of about 150 μg/kg/day during puberty to about 25 μg/kg/day by age 55.114 During this process there is a reduction in GH pulse amplitude, but little change in GH pulse frequency.116 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.117118 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.119 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.120121 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 (GSHs) 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.122 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),123 treatment of children with idiopathic growth hormone deficiency,124 management of adult-onset growth hormone deficiency/insufficiency and other conditions requiring GH replacement therapy (GHRT),125125 regeneration of pituitary function and delay its functional decline during aging124126
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.127 The following year, Wehrenberg and Ling128 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 daltons129 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).130
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.131132 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.133 Thus, modification of both pulse amplitude and frequency of GH secretion results from Sermorelin administration.134 After sermorelin stimulates the release of GH from the pituitary gland, it increases synthesis of IGF-1 in the liver and peripheral tissues.134
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.135
Sermorelin is readily degraded after reaching the bloodstream, having a biological half-life of approximately 10-20 min.136 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.137 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.138
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.139
To exert all its beneficial effects, Sermorelin requires a functioning pituitary and a host of peripheral tissues.140141 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.140
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.142 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.143
- Quality of life parameters including general well-being (P < 0.05) and libido (P < 0.01) significantly improved in men receiving sermorelin therapy.144
- Youthful concentrations and patterns of serum hGH were restored in older persons by daily injections of GRF (sermorelin).145
- Body composition improved after regular administration of GRF for 90 days resulting in increased muscle mass, increased total body water and decreased visceral fat.146
- Quality of sleep improved as indicated by extended Stage IV and Slow Wave Sleep in men.147
Symptoms 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.148
Diagnosis of Adult Growth Hormone Deficiency
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.111
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 physican 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.149 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).150151 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.152 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.
- 1. United States Pharmacopeia, Chapter 795. Pharmaceutical Compounding-Nonsterile Preparations. Revision Bulletin, Official January 1, 2014. http://www.usp.org/sites/default/files/usp_pdf/EN/gc795.pdf
- 2. Historica Canada, People, James Bertram Collip 2008 July. Bliss M. http://thecanadianencyclopedia.com/en/article/james-bertram-collip/
- 3. Int J Fertil Womens Med. 2003 May-Jun;48(3):106-10; discussion 137-8. Impact of WHI conclusions and ACOG guidelines on clinical practice. Gass M.
- 4. Hayes L et al. "Diurnal Variation of Cortisol, Testosterone, and Their Ratio in Apparently healthy Males". Sport Spa;9(1):5-13.
- 5. The Mayo Clinic Mayo Foundation for Medical Education and Research 'Male hypogonadism' http://www.mayoclinic.com/health/male-hypogonadism/DS00300/DSECTION=causes
- 6. Kucinskas L, just W. "Human male sex determination and sexual differentiation: Pathways, molecular interactions and genetic disorders". Medicina. 2005;41(8):633-640.
- 7. Beauchet O. "Testosterone and cognitive fucntion: current lcinical evidence of a relationship". European Journal of Endocrinology. 2006;155:773-781
- 8. Isidori AM, Giannetta E. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis". Clinical Endocrinology. 2005;63:280-93.
- 9. "Menopause". Fact Sheets. nebraska Department of Health and Human services, Office of Women's and Men's Health.
- 10. "Menstruation and the Menstrual Cycle". Fact Sheets. U.S. Department of Health and Human SErvices, Office on Women's Health. 21 Oct 2009.
- 11. Miller M, et al. "Theoretical basis for the benefit of postmenopausal estrogen substitution." Experimental Gerontology. 1999;34:587-604.
- 12. 5. Smith P. "A Comprehensive Look at Hormones and the Effects of hormone Replacement".What You Must Know About Women's Hormones: Your Guide to Natural Hormone Treatment for PMS, Menopause, Osteoporosis, PCOS, and More. Square One Publishers. 28 Nov 2009: Chapter 41.
- 13. 4.Obstet Gynecol. 2012 Oct;120(4):833-42. Sexual function in older women after oophorectomy. Erekson EA, Martin DK, Zhu K, Ciarleglio MM, Patel DA, Guess MK, Ratner ES.
- 14. Erekson E, et al. "Sexual function in older women after oophorectomy". Obstetrics and Gynecology. Oct 2012;120(4):833-42.
- 15. Obstet Gynecol. 2012 Oct;120(4):833-42. Sexual function in older women after oophorectomy. Erekson EA, Martin DK, Zhu K, Ciarleglio MM, Patel DA, Guess MK, Ratner ES.
- 16. J Clin Endocrinol Metab. 2012 Mar;97(3):756-9. Misconception and concerns about bioidentical hormones used for custom-compounded hormone therapy. Bhavnani BR, Stanczyk FZ.
- 17. Miller M, et al. "Theoretical basis for the benefit of postmenopausal estrogen substitution." Experimental Gerontology. 1999;34:587-604.
- 18. Want C, Alexander G, et al. "Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study." Journal of Clinical Endocrinology & Metabolism. Oct 1996;81(10):3578-83.
- 19. Bhattacharya RK, Khera M, et al. "Effect of 12 months of testosterone replacement therapy on metabolic syndrome components in hypogonadal men: data from the Testin Registry in the US". BMC Endocrine Disorders. 2011;11(18).
- 20. Garber J, et al. “Clinical Practice Guidelines for Hypothyroidism in Adults”. Thyroid. 2012;22(12):1200-35.
- 21. Longo D, et al. “341: Disorders of the Thyroid Gland”. Harrison’s Principles of Internal Medicine. (18th ed.). New York: McGraw-Hill.
- 22. DeRuiter J. “Thyroid Hormone: Thyroid Pathology.” PYPP 5260-Endocrine Module. Auburn University. 2002.
- 23. “Hypothyroidism.” Hypothyroidism Patient Brochure. American Thyroid Association. 2014.
- 24. Zhang J, Lazar M. “The Mechanism of action of Thyroid Hormones.” Annual Review of Physiology.” 2000;62:439-66.
- 25. Kahaly G, Dilmann W. “Thyroid Hormone Action in the Heart.” Endocrine Reviews. Jul 1 2013;26(5):704-728.
- 26. Fazio S et al. “Effects of Thyroid Hormone on the Cardiovascular System.” Recent Progress in Hormone Research. 2004;59:31-50.
- 27. Shin D, Osborne TF. “Thyroid Hormone Regulation and Cholesterol Metabolism Are Connected through Sterol Regulatory Element-binding Protein-2 (SREBP-2).” The Journal of Biological Chemistry. 2003;278:1-5.
- 28. Lowrance J. Cardiac Effects of Hypothyroidism and Hyperthyroidism: Heart Problems caused by Thyroid Disease. Self-published eBook. 2014.
- 29. Luigi P, et al. “Alzheimer’s disease: the cholesterol connection”. Neuroscience. Nature Publishing Group. 2003 Apr;6(4):345-51.
- 30. Tan Z, Vasan R. “Thyroid Function and Alzheimer’s Disease.” Journal of Alzheimer’s Disease. 2009;16:503-507.
- 31. “Kapaki E et al. “Thyroid function in patients with Alzheimer’s disease treated with cholinesterase inhibitors.” ACTA Neurobiologiae Experimentalis. 2003;63:389-392.
- 32. Armour Thyroid package insert. St. Louis, MO: Forest Pharmaceuticals Inc.; 2012 Aug.
- 33. Professional Guide to Drugs-A Reference for Doctors, Nurses, Dentists, Pharmacists-Anyone Who Prescribes, Administers, or Takes Medicines. Cal State Long Beach Library: Intermed Communications Books. 1982. P. 592.
- 34. ”Liothyronine-Description.” Clinical Pharmacology. 2013 Aug 23. Web.
- 35. Us Pharmacopeia Natural Formulary USP 37 N32 2014 Volume 3 May 1, 2014. The United States Pharmacopeial Convention. 2014.
- 36. Women’s International Pharmacy. ”Thyroid Hormone Therapy Options”. 2014. Web.
- 37. The United Pharmacopeial convention, USP 36 Official Monographs, Thyroid p 5383. December, 2013.
- 38. Armour Thyroid (thyroid tablets) package insert. St. Louis, MO: Forest Pharmaceuticals, Inc.; 2011 Jan.
- 39. Shomon M. “Armour Thyroid’s Spring 2009 Reformulation Causing Problems”. About.Thyroid. About.com. 2014 Aug 18. Web.
- 40. Wiersinga W. “do we need still more trials on T4 and T3 combination therapy in hypothyroidism?” European Journal of Endocrinology. 2009;161(6):955-9.
- 41. “Description-Desiccated Thyroid. Clinical Pharmacology Database. Elsevier. Aug 1 2013.
- 42. Zhang J, Lazar M. “The Mechanism of action of Thyroid Hormones.” Annual Review of Physiology.” 2000;62:439-66.
- 43. Friedman, Theodore, MD Ph.D. “The 15% Rule of Who Should Get T4/T3 Combination.” www.goodhormonehealth.com Good Hormone Health. 2001.
- 44. ”The Top 10 Most Prescribed Drugs”. WebMD. WebMD, LLC.
- 45. Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, Morreale de Escobar G. “Review: Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. Journal of Clinical Endocrinology and Metabolism. 2005;90:4946-54.
- 46. ”Liothyronine USP Safety Data Sheet”. Reference Standards. US Pharmacopeia. 2009 Apr 10;3:5659-65. Revised: 2012 Nov 26.
- 47. ”Liothyronine Sodium-liothyronine sodium tablet. Carilion Materials Management. 2014 May.
- 48. Vanderpump M, et al. “Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism.” British Medical Journal. 1996 Aug 31;313:539-44.
- 49. Weissel M. “Administration of thyroid hormones in therapy of psychiatric illnesses.” Acta Medical Austriaca. 1999;26(4):129-31.
- 50. Robinson P. Recovering With T3: My Journey from Hypothyroidism to Good Health Using the T3 Thyroid Hormone. Elepahant in the Room Books. 30 Nov 2011.
- 51. Nygaard B et al. “Effect of combination therapy with thyroxine (T4) and 3,5,3’-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study.” European Journal of Endocrinology. 2009;161(6):895-902.
- 52. Bunevicius R, Kazanavicius G, Zalankevicius R, Prange AJ Jr. “Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. New England Journal of Medicine. 1999;340: 424-9.
- 53. Clyde P, et al. “Combined Levothyroxine Plus Liothyronine Compared with Levothyroxine Alone in Primary Hypothyroidism: A Randomized Controlled Trial. ” Journal of the American Medical Association. 2003;290:2952-8
- 54. ”Liothyronine USP Safety Data Sheet”. Reference Standards. US Pharmacopeia. 2009 Apr 10;3:5659-65. Revised: 2012 Nov 26.
- 55. British Thyroid Association Executive Committee. “Armour Thyroid (USP) and combined thyroxine/tri-iodothyronine as Thyroid Hormone Replacement.” A Statement from the British Thyroid Association Executive Committee, November 2007. Nov 2007.
- 56. Friedman, Theodore, MD Ph.D. “The 15% Rule of Who Should Get T4/T3 Combination.” www.goodhormonehealth.com. Good Hormone Health. 2001.
- 57. ”DIO2.” Hugo Gene Nomenclature Committee. EMBL-EBI.
- 58. “DIO2 deiodinase, iodothyronine, type II [Homo sapiens (human)].” Genes & Gene Expression Database, National Center for Biotechnology Information. U.S. National Library of Medicine. Bethesda, MD.
- 59. Gavin L, Castle J, McMahon F, Martin P, Hammond M, Cavalieri R. “Extrathyroidal Conversion of Thyroxine to 3, 3’, 5’-Triiodothyronine (Reverse-T3) and to 3, 5, 3’-Triiodotyronine. Journal of clinical endocrinology and Metabolism. 1977;44(4):733-42.
- 60. Milner M. “Hypothyroidism: Optimizing medication with Slow-Release Compounded thyroid Replacement.” International Journal of Pharmaceutical Compounding. 2005;9(4):268-273.
- 61. ”Liothyronine USP Safety Data Sheet”. Reference Standards. US Pharmacopeia. 2009 Apr 10;3:5659-65. Revised: 2012 Nov 26.
- 62. Robinson P. Recovering With T3: My Journey from Hypothyroidism to Good Health Using the T3 Thyroid Hormone. Elephant in the Room Books. 30 Nov 2011.
- 63. Myhill S. “Thyroid-the correct prescribing of thyroid hormones.” Dorctor Myhill: Empowering you to Recover your Health. Sarah Myhill Limited. Upper Weston, Llangunllo, Knighton-Powys, Wales, United Kingdom.
- 64. Milner M. “Hypothyroidism: Optimizing medication with Slow-Release Compounded thyroid Replacement.” International Journal of Pharmaceutical Compounding. 2005;9(4):268-273.
- 65. British Thyroid Association Executive Committee. “Armour Thyroid (USP) and combined thyroxine/tri-iodothyronine as Thyroid Hormone Replacement.” A Statement from the British Thyroid Association Executive Committee, November 2007. Nov 2007.
- 66. US Pharmacopeia Natural Formulary USP 37 N32 2014 Volume 3 May 1, 2014. The United States Pharmacopeial Convention. 2014.
- 67. Vu N, et al. ”Compounding Slow-Release Pharmaceuticals”. “International Journal of Pharmaceutical Compounding. 2009;13(2):144-5
- 68. “Hypothyroidism: Optimizing medication with Slow-Release Compounded thyroid Replacement.” International Journal of Pharmaceutical Compounding. 2005;9(4):268-273.
- 69. Lapthorn, A.J., et al., Crystal structure of human chorionic gonadotropin. Nature, 1994. 369(6480): p. 455-61.
- 70. Rahman, N.A. and C.V. Rao, Recent progress in luteinizing hormone/human chorionic gonadotrophin hormone research. Mol Hum Reprod, 2009. 15(11): p. 703-11.
- 71. Rao, C.V., Differential properties of human chorionic gonadotrophin and human luteinizing hormone binding to plasma membranes of bovine corpora lutea. Acta Endocrinol (Copenh), 1979. 90(4): p. 696-710.
- 72. Choi, J. and J. Smitz, Luteinizing hormone and human chorionic gonadotropin: origins of difference. Mol Cell Endocrinol, 2014. 383(1-2): p. 203-13.
- 73. Casarini, L., et al., LH and HCG action on the same receptor results in quantitatively and qualitatively different intracellular signalling. PLoS One, 2012. 7(10): p. e46682.
- 74. Coviello, A.D., et al., Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab, 2005. 90(5): p. 2595-602.
- 75. Hsieh, T.C., et al., Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol, 2013. 189(2): p. 647-50.
- 76. Kim, S.O., et al., Penile growth in response to human chorionic gonadotropin (HCG) treatment in patients with idiopathic hypogonadotrophic hypogonadism. Chonnam Med J, 2011. 47(1): p. 39-42.
- 77. Jin, J.M. and W.X. Yang, Molecular regulation of hypothalamus-pituitary-gonads axis in males. Gene, 2014. 551(1): p. 15-25.
- 78. Package Insert for Pitocin and Syntocinon from www.drugs.com accessed December 2007.
- 79. Lee HJ, Macbeth AH, Pagani JH, Young WS (June 2009). "Oxytocin: the great facilitator of life". Prog. Neurobiol. 88 (2): 127–51.
- 80. De Dreu CK, Greer LL, Van Kleef GA, Shalvi S, Handgraaf MJ (January 2011). "Oxytocin promotes human ethnocentrism". Proc. Natl. Acad. Sci. U.S.A. 108 (4): 1262–6
- 81. Malik AI, Zai CC, Abu Z, Nowrouzi B, Beitchman JH (July 2012). "The role of oxytocin and oxytocin receptor gene variants in childhood-onset aggression". Genes Brain Behav. 11 (5): 545–51.
- 82. Guinn, D. A.; Davies, J. K.; Jones, R. O.; Sullivan, L.; Wolf, D. (2004). "Labor induction in women with an unfavorable Bishop score: Randomized controlled trial of intrauterine Foley catheter with concurrent oxytocin infusion versus Foley catheter with extra-amniotic saline infusion with concurrent oxytocin infusion". American Journal of Obstetrics and Gynecology 191 (1): 225–229.
- 83. Prog Neurobiol. 2009 Jun;88(2):127-51. Epub 2009 Apr 10. Oxytocin: the great facilitator of life. Lee HJ, Macbeth AH, Pagani JH, Young WS 3rd. Section on Neural Gene Expression, NIMH, NIH, DHHS, Bethesda, MD 20892, USA.
- 84. Renfrew MJ1, Lang S, Woolridge M. "Oxytocin for promoting successful lactation." Cochrane Database Syst Rev. 2000;(2):CD000156
- 85. Neville, Margaret C. "Lactogenesis: The Transition from Pregnancy to Lactation Oxytocin and Milk Ejection." 1998. University of Colorado Denver. Department of Physiology
- 86. Applied Therapeutic: The Clinical Use of Drugs. Sixth Edition; 1997: 44-29.
- 87. Cabanac M, Pfaff DW, Ogawa S, et al. Neural oxytocinergic systems as genomic targets for hormones and as modulators of hormone-dependent behaviors. Results Probl Cell Differ 1999;26:91-105.
- 88. Insel TR, O’Brien DJ, Leckman JF (1999): Oxytocin, vasopressin, and autism: is there a connection? Biol Psychiatry 45:145-147.
- 89. Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR, Mosovich S (2003): Oxytocin infusion reduces repetitive behaviors in adults with autistic and Aspberger’s disorders. Neuropsychopharmacology 28:193-198.
- 90. Modahl C, Green L, Fein D, Waterhouse L, Feinstein C, Morris M, Levin H (1998): Plasma oxytocin levels in autistic children. Biol Psychiatry 43:270-277.
- 91. Waterhouse L, Fein D, Modahl C (1996): Neurofunctional mechanisms in autism. Psychol Rev 103:457-489.
- 92. McCarthy MM, Altemus M (1997): Central nervous system actions of oxytocin and modulation of behavior in humans. Mol Med Today 3:269-275.
- 93. Panksepp J (1992): Oxytocin effects on emotional processes: separation distress, social bonding, and relationships to psychiatric disorders. Ann NY Acad Sci 652:243-252.
- 94. Popik P, Vetulani J, van Ree JM (1992): Low doses of oxytocin facilitate social recognition in rats. Psychopharmacology (Berl) 106:71-74
- 95. Zhonghua Nan Ke Xue. 2011 Jun;17(6):558-61. Oxytocin and male sexual function.
- 96. Argiolas, A and Melis, M. Cagliari. Oxytocin-Induced Penile Erection, Role of Nitric Oxide, Italy: 247; 1995. Plenum Press, New York.
- 97. Pedersen, C.A., Boccia, M.A. “Oxytocin Maintains as Well as Initiates Female Sexual Behavior: Effects of a Highly Selective Oxytocin Antagonist”), 2002. Hormones and Behavior. Volume 41, Issue 2, March 2002, Pages 170–177.
- 98. Oxytocin Cellular and Molecular Approaches in Medicine and Research. Increased female sexual response after Oxytocin. Anderson-Hunt M and Dennerstein L. Brit Med J 309:929: 236; 1994 Plenum Press, New York.
- 99. Carmichael MS, Humbert R, Dixen J, et al. Plasma Oxytocin increases in the human sexual response. J Clin Endcrinol Metab, 1987. 64:27-31.
- 100. Pedersen, C.A., 2002. Oxytocin increases sexual receptivity and counteracts impotence, (Arletti, 1997)
- 101. Isolated growth hormone deficiency. Genetics Home Reference. February 2012. Retrieved 12 December 2017
- 102. “Growth hormone deficiency”. Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2016. Retrieved 12 December 2017.
- 103. “Growth Hormone Deficiency”. NORD (National Organization for Rare Disorders). 2016. Retrieved 12 December 2017.
- 104. Degenerative neurologic disease in patients formerly treated with human growth hormone. Report of the Committee on Growth Hormone Use of the Lawson Wilkins Pediatric Endocrine Society, May 1985. J Pediatr. 1985 Jul; 107(1):10-2).
- 105. Vitiello MV, Schwartz RS, Moe KE, Mazzoni G, Merriam GR. 2001 Treating age-related changes in somatotrophic hormones, sleep, and cognition. In Health, age, hormones, sleep, and cognition Dialogues in Clinical Neuroscience – Vol 3. No. 3.
- 106. Rosen T, Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336:285–288
- 107. Toogood AA, Beardwell CG, Shalet SM. 1994 The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism. Clin Endocrinol (Oxf). 41:511–516.
- 108. Ho, KKY, Hoffman,DM. 1995 Defining growth hormone deficiency in adults. Metabolism 44:[Suppl 4]:91–96
- 109. DeBoer H, Blok GJ, Van der Veen EA. 1995, Clinical aspects of growth hormone deficiency in adults. Endocr Rev 16:63–86
- 110. Korbonits M, Besser M 1996 Diagnosis of growth hormone deficiency in adults. Horm Res 46:174–182
- 111. Molitch ME, Clemmons DR, Malozowski S, et al. 2006. “Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline”. J. Clin. Endocrinol. Metab. 91 (5): 1621–34.
- 112. Vitiello MV, Schwartz RS, Moe KE, et al. Treating age-related changes in somatotrophic hormones, sleep, and cognition. In Health, age, hormones, sleep, and cognition Dialogues in Clinical Neuroscience – Vol 3. No. 3. 2001.
- 113. Russell-Aulet M, Jaffe CA, Demott-Friberg R, Barkan AL. 1999, In vivo semiquantification of hypothalamic growth hormone-releasing hormone (GHRH) output in humans: Evidence for relative GHRH deficiency in aging. J Clin Endocrinol Metab. 84:3490.
- 114. Melmed S. Physiology of growth hormone [online] 2006. Up to Date Accessed 8 Sep 2006. URL: http://www.uptodate.com.).
- 115. Russell-Aulet M, Dimaraki EV, Jaffe CA, DeMott-Friberg R, Barkan AL. 2001. Aging-related growth hormone (GH) decrease is a selective hypothalamic GH-releasing hormone pulse amplitude mediated phenomenon. J Gerontol A Biol Sci Med Sci. 56(2):M124-9.
- 116. Merriam GR, Schwartz RS, Vitiello MV. Growth hormone-releasing hormone and growth hormone secretagogues in normal aging. Endocrine. 2003 Oct; 22(1):41-8.
- 117. Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogol AD, Kaiser DL, Thorner MO. 1987. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab. 64(1):51-8.
- 118. Merriam GR, Kletke M, Barsness S, et al. 2000. Growth hormone-releasing hormone in normal aging: An Update. Today’s Therapeutic Trends. 18:335–54.
- 119. Merriam GR, Buchner DM, Prinz PN, Schwartz RS, Vitiello MV. 1997. Potential applications of GH secretagogues in the evaluation and treatment of the age-related decline in growth hormone secretion. Endocrine. 7(1):49-52.
- 120. Anawalt BD, Merriam GR 2001. Neuroendocrine aging in men. Andropause and somatopause Endocrinol Metab Clin North Am. 30(3):647-69.
- 121. Merriam GR, Cummings DE. Growth hormone and growth hormone secretagogues in adults. In: Meikle W, editor. Endocrine replacement therapy in clinical practice. Totowa, NJ: Humana Press; 2003. Pp. 63–94.
- 122. Wehrenberg WB, Ling N. 1983. "In vivo biological potency of rat and human growth hormone-releasing factor and fragments of human growth hormone-releasing factor". Biochem Biophys Res Commun. 115 (2): 525–530.
- 123. Prakash, A. and Goa KL. 1999, Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency. BioDrugs, 12(2): p. 139-57.
- 124. Kirk JM, Trainer PJ, Majrowski WH, Murphy J, Savage MO, Besser GM. 1994. Treatment with GHRH(1-29)NH2 in children with idiopathic short stature induces a sustained increase in growth velocity. Clin Endocrinol (Oxf). 41(4):487-93.
- 125. Walker, R.F., 2006. Sermorelin: a better approach to management of adult-onset growth hormone insufficiency? Clin Interv Aging, 1(4): p. 307-8.
- 126. Walker, R.F., 2006. Sermorelin: a better approach to management of adult-onset growth hormone insufficiency? Clin Interv Aging, 1(4): p. 307-8.
- 127. Rivier J, Spiess J, Thorner M, Vale W. 1982 Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature, 300:276-278.
- 128. Wehrenberg WB, Ling N (1983). "In vivo biological potency of rat and human growth hormone-releasing factor and fragments of human growth hormone-releasing factor". Biochem Biophys Res Commun. 115 (2): 525–530.
- 129. Drug Bank, Sermorelin, Identification. Drug created on June 13, 2005 07:24 / Updated on January 20, 2014 14:07 http://www.drugbank.ca/drugs/DB00010
- 130. Drug Bank, Sermorelin, Identification. Drug created on June 13, 2005 07:24 / Updated on January 20, 2014 14:07 http://www.drugbank.ca/drugs/DB00010
- 131. Chen, R.G., et al., 1993. A comparative study of growth hormone (GH) and GH-releasing hormone (1-29)-NH2 for stimulation of growth in children with GH deficiency. Acta Paediatr Suppl, 388: p. 32-5; discussion 36.
- 132. Perez-Romero, A., et al., 1999. Effect of long-term GHRH and somatostatin administration on GH release and body weight in prepubertal female rats. J Physiol Biochem, 55(4): p. 315-24.
- 133. Tannenbaum, G.S. and Ling N. 1984. The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology, 115(5): p. 1952-7.
- 134. Tauber, M.T., et al., 1993. Growth hormone (GH) profiles in response to continuous subcutaneous infusion of GH-releasing hormone(1-29)-NH2 in children with GH deficiency. Acta Paediatr Suppl, 388: p. 28-30; discussion 31.
- 135. Howard AD, Feighner SD, Cully DF et al. 1996, A Receptor in Pituitary and Hypothalamus That Functions in GH release. Science. Vol. 273, Issue 5277, pp. 974-977
- 136. Esposito, P., et al., 2003. PEGylation of growth hormone-releasing hormone (GRF) analogues. Adv Drug Deliv Rev, 55(10): p. 1279-91.
- 137. Kirk JM, Trainer PJ, Majrowski WH, Murphy J, Savage MO, Besser GM. 1994. Treatment with GHRH(1-29)NH2 in children with idiopathic short stature induces a sustained increase in growth velocity. Clin Endocrinol (Oxf). 41(4):487-93.
- 138. Aitman, T.J., et al., 1989. Bioactivity of growth hormone releasing hormone (1-29) analogues after SC injection in man. Peptides, 10(1): p. 1-4.
- 139. Steiger, A., et al., 1994. Growth hormone-releasing hormone (GHRH)-induced effects on sleep EEG and nocturnal secretion of growth hormone, cortisol and ACTH in patients with major depression. J Psychiatr Res, 28(3): p. 225-38.
- 140. Mayo, K.E., et al., 1995. Growth hormone-releasing hormone: synthesis and signaling. Recent Prog Horm Res, 50: p. 35-73.
- 141. Ceda, G.P., et al. 1987. The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis: evidence for rapid inhibition of GHRH-elicited GH release by insulin-like growth factors I and II. Endocrinology, 120(4): p. 1658-62.
- 142. Drug Bank, Sermorelin, Pharmacology. Drug created on June 13, 2005 07:24 / Updated on January 20, 2014 14:07 http://www.drugbank.ca/drugs/DB00010
- 143. Barron JL, Coy DH, Millar RP Growth hormone responses to growth hormone-releasing hormone (1-29)-NH2 and a D-Ala2 analog in normal men. Peptides. 1985 May-Jun, 6(3):575-577.
- 144. Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advancing men and women. J Clin Endocrinol Metab. 1997 May; 82(5):1472-9.
- 145. Corpas E, Harman SM, Pineyro MA et al. Growth hormone (GH)-releasing hormone–(1-29) twice daily reverses the decreased GH and insulin-like growth factor-I levels in old men. J Clin Endocrinol Metab. 1992, 75:530-535.
- 146. Veldhuis JD, Patrie JM, Frick K, et al. Administration of recombinant GHRH for 3 months reduces abdominal visceral fat mass and icnreases physical performance measures in postmenopausal women. Eur J Endocrinol. 2005, 153:669-677.
- 147. Steiger A, Guldner J, Hemmeter U, Rothe B, Wiedemann K, Holsboer F. Effects of growth hormone-releasing hormone and somatostatin on sleep EEG and nocturnal hormone secretion in male controls. Neuroendocrinology. 1992 Oct; 56(4):566-73.
- 148. Toogood AA, O’Neill PA, Shalet SM. 1996. Beyond the Somatopause: Growth Hormone Deficiency in Adults Over the Age of 60 Years. J Clin Endocrinol Metab, 81: 460-465
- 149. Merriam GR, Kletke M, Barsness S, et al. 2000. Growth hormone-releasing hormone in normal aging: An Update. Today’s Therapeutic Trends. 18:335–54
- 150. Merriam GR. Growth hormone as anti-aging therapy, and other emerging (and submerging) indications:Clinical Endocrinology Update. The Endocrine Society; Chevy Chase, MD. 2002.
- 151. Merriam GR, Schwartz RS, Vitiello MV. 2003. Growth hormone-releasing hormone and growth hormone secretagogues in normal aging. Endocrine. 22(1):41-8.).
- 152. Merriam GR, Barsness S, Buchner D, et al. 2002. Growth hormone-releasing hormone treatment in normal aging. J Anti Aging Med. 4:1–13.