Kent Holtorf, MD and Erika T. Schwartz, MD
The study and use of hormones have long been the domains of endocrinology, which is primarily focused on the pathologic phenomena encountered in the human body as they relate to hormones. No specific field in medicine has been designated to study and analyze the effects of hormones on wellness and disease prevention. As the field of wellness and disease prevention expands rapidly, it behooves the primary care practitioner, the first physician contact between the patient and the health care system, to become conversant and comfortable with hormone treatments as they relate to wellness and disease prevention.
Extensive scientific literature addresses the crucial role hormones play in the physiologic processes that maintain homeostasis. Much controversy surrounds the clinical use of various hormone therapies to support and maintain these processes in the aging patient. This article attempts to clarify some of the confusion and controversy surrounding estrogen, progesterone, testosterone, growth hormone, and thyroid hormones and discuss their roles as supported by the present state of evidence in disease prevention and aging as they apply to the primary care practice.
Hormones represent specific proteins produced by the human endocrine organs: pituitary, adrenals, thyroid, testes, and ovaries. Our focus is limited to estrogen, progesterone, testosterone, growth hormone, and thyroid. In health, all hormones are individually and wholly integral participants to the maintenance of cellular function and homeostasis. Hormone levels undergo diurnal variation and levels change in response to our environment, thought processes, stress levels, and food intake. Environmental toxins, medications, and pollutants also significantly affect hormone balance.
With the aging process, hormone levels decrease naturally. As these levels decline, problems with health maintenance arise. The diminution in hormone levels that occurs as a result of aging may or may not be compounded by concomitant disease states and environmental factors. In this article, we discuss age-related hormone loss and supplementation therapies for age-related hormonal deficiencies as possible firstline therapeutic modalities to be considered in our search to improve quality of life, prevent chronic illnesses, and maintain wellness.
Testosterone is the primary androgen produced by the testes and it plays an essential role in the health of the male. Beyond determining the male sex characteristics, testosterone is a determinant of muscle strength, bone mass, libido, potency, and spermatogenesis.
Androgen deficiency includes but is not limited to symptoms of decreased body hair, reduction in muscle mass and strength, increase in fat mass, decreased hematocrit, decreased libido, erectile dysfunction, infertility, osteoporosis, depression, and mood changes. Androgen deficiency may occur secondary to testicular or pelvic trauma or surgical removal, hypogonatropic hypogonadism, or with normal aging.
The normal aging process leads to adult hypogonadism with a decrease in levels of testosterone with age and the development of some or all of the symptoms enumerated above. The condition of androgen deficiency in aging is also known as andropause. Androgen deficiency or hypogonadism is the result of subnormal production of testosterone by the testes. Its prevalence in healthy males over the age of 40 is demonstrated in observational studies, but there is no agreed upon blood level that defines deficiency. Common causes of hypogonadism include but are not limited to:
Primary testicular failure Klinefelter syndrome Cryptorchidism Orchitis Trauma HIV/AIDS Myotonic muscular deficiency Retroperitoneal fibrosis Aging Hypogonadotropic hypogonadism Kallman syndrome Prader-Willi syndrome Idiopathic hypopituitarism Pituitary tumors Suprasellar tumors Hemochromatosis Inflammatory, traumatic, vascular lesions of pituitary and hypothalamus Obesity Severe chronic illnesses Medication Andropause
The risk of having low testosterone levels is significantly higher in men with hypertension (RR 1.84), hyperlipidemia (RR 1.47), diabetes (RR 2.09), obesity (RR 2.38) and asthma or chronic obstructive pulmonary disease (RR 1.40) than in men without these conditions. The prevalence of hypogonadism (defined as a total testosterone level below 300ng/dL) in 2162 men aged 45 years or older presenting to primary care offices was 38.7% in a study by Mulligan and colleagues.
Perhaps the most significant controversy related to testosterone is the debate over its role in prostate health. For more than 60 years, traditional medical wisdom regarded testosterone as a significant risk factor for prostate hypertrophy and assumed that high testosterone levels served as fuel for prostate cancer. Hormone blockade and or estrogen therapy are still standard of care for prostate cancer therapy even today. Clinicians have hesitated to treat aging males with testosterone because of the belief that high levels of testosterone cause prostate cancer or speed up its growth. More than a decade ago, Shippen, Fryer, and Wright took the view that testosterone is actually protective and should be used. A ground-breaking study released in November 2007 provided a whole new set of data and a new perspective on testosterone. The results of this large-scale prospective study revealed that high endogenous levels of testosterone are associated with low mortality from all causes. The study suggests that low testosterone may be a predictive marker for those at high risk of cardiovascular disease.
Shores and colleagues investigated the correlation between testosterone levels (defined as total testosterone <250 ng/dL or free testosterone <0.75 ng/dL) and mortality in 858 males followed for up to 8 years. The results demonstrated that men with low circulating levels of testosterone had an 88% increased risk of mortality.
Cardiovascular Experimental studies suggest that androgens induce coronary vasodilatation. A placebo-controlled double-blind (PCDB) study performed in the United Kingdom followed 46 men with stable angina randomized to receive either a 5-mg testosterone patch or placebo in addition to their current medicines for 12 weeks. Both groups were then monitored for changes in treadmill exercise time before the onset of myocardial ischemia. The results of the treatment group compared with the placebo group were statistically significant (22% improvement in exercise time before onset of ST depression) without effect on prostate-specific antigen (PSA), hemoglobin, lipids, or coagulation profile during the duration of the study. Low-dose supplemental testosterone treatment in men with chronic stable angina increased exercise time preceding induced myocardial ischemia as defined by ST depression on EKG.80 Testosterone replacement therapy has also been proven to reduce insulin resistance, visceral adiposity, and cardiovascular risk. Additionally, a relatively low testosterone, independent of adiposity, is a risk factor for insulin resistance and type II diabetes and vice versa (insulin resistance and diabetes mellitus II are risk factors for low testosterone).
Anemia Anemia is a frequent feature of male hypogonadism and antiandrogenic therapies. In a study that evaluated hemoglobin levels in 905 persons 65 years or older, of which 31 men and 57 women had anemia, hemoglobin levels were evaluated after 3 years. The participants were patients without cancer, renal insufficiency, or antiandrogenic treatments. Statistical evaluation of the results showed that older men and women with low testosterone levels had a higher risk of anemia.
Mood and quality of life There is a compelling need for therapies that prevent Alzheimer’s disease, defer its onset, slow its progression, and alleviate its symptoms. In a study that evaluated the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in male patients with Alzheimer’s disease and healthy elderly men, 16 male patients with Alzheimer’s disease and 22 healthy male controls were treated with testosterone and a placebo gel daily. Patients receiving testosterone had significant improvement in quality-of-life scores and the treatment was well tolerated. Testosterone had minimal effects on cognition and the treated group showed more numerical improvement and less decline in visuospatial functions.
Osteoporosis and musculoskeletal Untreated hypogonadism is a prominent cause of osteoporosis in men and bone mineral density significantly increases with testosterone treatment. Older men are as responsive to the anabolic effects of testosterone as young men. Testosterone induces skeletal muscle hypertrophy that leads to improved muscle strength in the leg as demonstrated in this study. A reciprocal change in lean and fat mass is observed but further studies are needed to determine the exact mechanism of change and the therapeutic doses needed for older men to obtain optimal results with minimum side effects.
Libido and sexual function Treatment with testosterone improved sexual function in hypogonadal males in this very small study as measured by frequency and duration of erection and frequency of ejaculation. More studies in this important area must be undertaken to provide much-needed information. Perceived risks associated with testosterone treatments and its abuse in the areas of athletic enhancement have caused much confusion without scientific basis.
Prostate cancer The connection between higher testosterone levels and growth of prostate cancer originated in 1941 with the publication of two papers by Huggins and colleagues. The data reported were based on one patient and, despite 67 years of subsequent studies that failed to establish scientific support for this theory, we are still faced with reluctance to treat men with testosterone supplementation for fear of giving them prostate cancer or fueling prostate cancer already present at a subclinical or microscopic level.
More than 430,000 men were part of longitudinal studies over the course of the past 67 years, and no well-designed study has ever shown a direct correlation between total testosterone levels and prostate cancer. A 2007 review out of Harvard concluded that:
Although there is yet to be a large, long term, controlled study on the effect of TRT [testosterone replacement therapy] on PCa [prostate cancer] risk, it should be abundantly clear that raising T [testosterone] in hypogonadal men has little, if any, impact on PCa risk or growth in the short to medium term. The withholding of TRT in men because of fear of PCa risk or progression is no longer tenable in an age of evidence-based medicine, because neither evidence nor theory supports this position.
This article reviewed the state of the evidence and, based on the prospective longitudinal studies, concluded that ‘‘men who develop prostate cancer do not have higher baseline testosterone levels and men with higher testosterone levels are at no greater risk for developing prostate cancer than men with lower testosterone levels.’’ The primary care physician needs to address each patient individually and decide on the use of testosterone based on more than just testosterone levels or fear of prostate cancer. Follow-up with serial blood tests and PSAs is still an important part of the clinical follow-up and should be used for the protection of the patient.
Aromatase One of the most important factors affecting testosterone levels in aging men is the enzyme aromatase, which is found in fat tissue. Aromatase converts testosterone into estrogen, thus changing the ratio of estrogen to testosterone. Men who have excessive body and abdominal fat are likely to have increased estrogen levels caused by aromatase activity. This condition has been linked to decreased insulin sensitivity and metabolic syndrome.
When a history and symptoms of hypogonadism are clear, the diagnosis is relatively easy. However, often the patient presents with nonspecific history and symptoms and an unremarkable clinical history, making the diagnosis more difficult. Clinically, the typical adult hypogonadism patient is above 50, fatigued, has difficulty building muscle in spite of consistent workout regimen, complains of unexplained weight gain, may be mildly depressed, and may experience erectile dysfunction and loss of libido. In this clinical setting without diagnosable disease, the diagnosis of a relative age-related adult-onset hypogonadism is gaining popularity and treatment with testosterone is becoming more common in the integrative medicine and urology fields.
Thus, it becomes important for the primary care physician, who is the first line of diagnosis and treatment, to feel comfortable with the use of testosterone as a viable and safe short- and medium-term option in the therapeutic armamentarium of healthy aging and wellness preservation. Understanding and considering hypogonadism in every adult aging male is an integral part of prevention and wellness.
Primary testicular failure is associated with elevated follicle-stimulating hormone and luteinizing hormone levels. A baseline PSA and a complete blood cell count should be obtained before starting testosterone supplementation. Estrogen, progesterone, and dihydrotestosterone levels may also be of value. There is no agreed total or free testosterone cut-off level to define testosterone deficiency. Total testosterone is the most common measure of androgen activity, but is a poor indicator of tissue activity, demonstrating little correlation with clinical status, and is an unreliable indicator of response to therapy.
Free testosterone is a more accurate indicator of hypogonadism, but normal ranges for total and free testosterone vary widely among laboratories, even among those using the same assay, and the reference ranges show little or no correlation to clinical findings. When testing the testosterone levels of a patient who is considering testosterone supplementation to maintain and improve wellness, it is unusual to have available prior testosterone levels when that patient was younger, healthier, and symptom free. Thus, a result that appears to be within normal range may not necessarily reflect what is normal for that particular patient. This situation must be taken into account since it emphasizes the importance of clinical assessment and patient involvement in the decision to treat. The use of population-based statistically determined normal testing ranges is also limited by the fact that the average testosterone level in men today is less than the average level in men of the same age 15 years ago. This concerning fact is possibly due to environmental suppression of the hypothalamic-pituitary-testicular axis and may also be a contributing factor to diminished sperm counts and increased incidence of infertility.105 Testosterone levels decrease with age and illness. Typically, men with hypogonadotropic hypogonadism have low plasma testosterone and luteinizing hormone levels. Prolactin levels should be checked if the total testosterone level is below 250 ng/dL to rule-out a pituitary tumor.
Fifty percent of circulating testosterone is bound to sex hormone–binding globulin, which directly affects free testosterone levels. Free testosterone levels can be obtained to clarify testosterone status. However, variations are greater among free testosterone assays than among total testosterone assays. Also, reference ranges are not as standardized for free testosterone assays as they are for total testosterone assays. When borderline levels of testosterone are found, or the clinical picture and the blood tests disagree, a low or low-normal free or total testosterone level may be used to support a clinical diagnosis of androgen deficiency, but should not be used to exclude it.
Testosterone supplementation has gained popularity over the past 20 years. The benefits of testosterone supplementation include improved energy, greater muscle mass, increased stamina, greater strength, increased confidence, greater motivation, and enhanced libido.
Present formulations of testosterone include the following:
Testosterone gel (Androgel)
Testosterone patches (Androderm)
Compounded testosterone creams or gels
Subcutaneous testosterone implants
While it is useful to follow PSA levels during the course of testosterone replacement and supplementation, it is more important to track the velocity PSA increase. There is often a slight bump, a rise above 4.0 ng/mL, or a sudden increase in PSA with the initiation of testosterone therapy, followed by a stable constant level. An increase in PSA more than 0.35 ng/mL per year warrants further evaluation and a referral to the urologist. While using testosterone in disease prevention and wellness is relatively new to the primary care field, it holds much promise and meets with much support and enthusiasm from patients. The data we reviewed and our clinical experience support the use of testosterone as a first-line hormone supplementation in the aging male. More research is needed to substantiate and define the parameters necessary for its long-term use. For now, as the esteemed Dr. Morgantaler said:
… the diagnosis of androgen deficiency requires only an ear attuned to the characteristic symptoms and blood test providing evidence of reduced levels of total or free testosterone. Treatment provides an opportunity for gratifying results, for patients and clinicians alike.
As the proportion of aging people continues to rapidly rise, reducing the burden of age-related diseases becomes increasingly important in primary care. A controversial hormone that is center stage in the debate over the use of hormone therapies in prevention and wellness is growth hormone.
Growth hormone, a single-chain polypeptide produced in the pituitary gland, has a wide range of metabolic and cellular effects. Growth hormone plays an important role in the regulation of body composition, lipid profiles, tissue repair, cardiac and neuronal functioning, and maintenance of bone mineral density. Growth hormone is secreted in pulsatile fashion, especially during stage III and IV deep sleep. It acts on liver and other tissues to stimulate the production of insulinlike growth factors (IGFs), including IGF-1, which is also known as somatomedin C, and the production of IGF-binding proteins (IGFBPs), which also have direct cellular actions. The most abundant IGFBP is IGFBP-3. A large percentage of growth hormone effects are mediated through IGF-1. Because of the pulsatile nature of growth hormone production and short half-life (20–50 minutes), routine serum growth hormone levels cannot be used to determine overall production. While there are many influences on the production of IGF-1, levels correlate with overall growth hormone production, are relatively stable in the serum, and are currently the best estimate of growth hormone production and effect. While a low IGF-1 is a strong indicator of abnormally low growth-hormone production, an IGF-1 level in the normal reference range does not rule out deficiency.
While there is considerable variation in growth hormone production among individuals of the same age, there is a progressive decline in average growth-hormone production and IFG-1 levels after age 20, with average levels declining by 30% to 60% by age 40 to 60, and by 50% to 80% after age 60. Low growth-hormone levels and production are associated with low quality of life as measured by numerous criteria, including the Nottingham Health Profile and the Psychologic General Well-Being Index. Gibney and colleagues reviewed 10 years of use of growth hormone in adult growth-hormone deficient patients and found it to be of significant benefit.
A large number of peer-reviewed research, including long-term randomized controlled trial data, has demonstrated that growth hormone replacement improves energy, strength, cardiac function, blood pressure, cholesterol levels, insulin sensitivity cognitive function, immunity, and psychologic well-being; decreases body fat; increases lean muscle; prevents and reverses heart disease; prevents and improves osteoporosis; and improves quality of life.
Controversial issues regarding growth hormone supplementation include the use of growth hormone as a therapeutic modality for age-related deficiency; the accuracy and necessity of commonly used stimulation testing when considering growth hormone usage in well patients; the need for guidelines for safe and effective treatment; and potential side effects of treatment.
The diagnosis of growth hormone deficiency is difficult for a number of reasons. As discussed, random serum growth-hormone levels are not indicative of the overall growth hormone production and, while IGF-1 levels do correlate with overall growth hormone production, IGF-1 levels lack sensitivity to detect significant deficiency (IGF-1 levels are often in the normal range even if a significant deficiency exists).
With growth hormone stimulation testing, serum growth-hormone levels are measured after a variety of agents and protocols are used to stimulate the release of growth hormone from the pituitary. Such tests are often promoted as the means of differentiating growth hormone deficiency from normal state. Many endocrinologists believe the diagnosis of adult growth-hormone deficiency can only be made with the use of growth hormone stimulation testing. Such testing has proven to be inaccurate, highly variable, nonphysiologic, and lacking adequate sensitivity to detect relative growth-hormone deficiencies. The use of arbitrary cutoffs to define abnormality does not correlate with response to therapy. Studies demonstrate that using the same agent to perform stimulation tests multiple times on one patient do not consistently produce congruous results, thus bringing the usefulness of the test into question. Side effects of stimulation testing include significant hypotension, venous thrombosis, nausea, and vomiting. Deaths and neurologic damage have also been reported.
Because stimulation tests are clinically and physiologically unreliable, they are also unreliable for determining growth hormone deficiency. Currently the most appropriate means of diagnosing age-related growth-hormone deficiency is clinical recognition and a low-normal (below the mean) IGF-1 level.
The adult age-related clinical syndrome of growth hormone deficiency includes increased fat mass, decreased muscle mass and strength, decreased bone density, elevated lipids, insulin resistance, decreased psychosocial well-being and depression, fatigue, increased social isolation, inability to handle stress, cardiovascular disease, memory decline, overall deterioration in quality of life, frailty, thin dry skin, increased wrinkles, and diminished exercise tolerance.
Clinicians commonly encounter these clinical symptoms in the aging patient. If considered appropriate by physician and patient, a 6-month therapeutic trial with growth hormone could be considered, dosed to keep IGF-1 levels in the upper quartile. Patients should be evaluated for symptomatic and metabolic improvements at a minimum at 3 and 6 months to decide if treatment should be continued.
The treatment of age-related adult growth-hormone deficiency remains controversial even though the literature reports significant benefits from growth hormone supplementation. The main sources of concern associated with growth hormone replacement in somatopause include, in no particular order, significant cost of therapy from $250 to $1500 per month (depending on dose and manufacturer), side effects of water retention resulting in joint pain and carpal tunnel syndrome, temporary reduction in insulin sensitivity, and theoretic risk of cancer. Most short-term side effects are diminished with reduction in dose. While there is a long-held theoretic belief of an increased risk of cancer, based on the growth hormone’s antiapoptotic and mitogenic effects, neither long-term nor short-term data support this theory. Conflicting data on the relationship between IGF-1 levels and the risk of cancer abound. Some frequently cited epidemiologic studies have found an increased correlation between elevated IGF-1 and breast, prostate, and colorectal cancers, while the majority of studies failed to document increased risk of cancer (or have shown a decreased risk) with increasing IGF-1 levels. In addition, one frequently cited study that did connect increased IGF-1 levels and cancer, by Chan and colleagues,150 is very controversial because the blood was stored for 5 to 15 years before it was tested. Also, IGF-1 levels in the highest quartile group were over three times the upper limit of normal for this age group, suggesting that IGF-1 in the patients studied may not have been measured accurately. Hankinson and colleagues149 found a trend for decreased risk of breast cancer in postmenopausal women with increased IGF-1 levels but an increased risk in premenopausal women. Palmqvist and colleagues151 reported increased association between IGF-1 and colon cancer, but a decreased risk of rectal cancer.
The secretion and regulation of IGF-1 is extremely complex and their reported association with cancer must also take into consideration numerous other potential confounding etiologic factors, whether environmental, nutritional, or other yet unidentified. Growth hormone stimulates the production of IGFBP-3, which has cancerprotective characteristics and may counteract increased risk of cancer associated with an increase in IGF-1, if present. There is evidence that tumors secrete IGF-1, which makes it a potential marker for cancer in some individuals and not necessarily a cause. Typical growth hormone supplementation for an age-related deficiency results in small increases in IGF-1 that remain in the normal age-matched references range, so risk would not be expected to be different than that for controls.
None of the long- and short-term studies have shown an increased risk of cancer, recurrent or de novo, with the use of growth hormone, and some of the studies have shown a decreased risk. Among these studies are studies on more than 19,000 children representing of 47,000 patient years of growth hormone treatment; a prospective study of 100 adult growth hormone–deficient patients followed for 1 to 4 years, a study of 910 children treated with growth hormone for 11 years, a study of 32 adults and children followed for up to 40 years treated with growth hormone (average 10.8 years); a study of 180 growth hormone–treated children followed for over 6 years with reduced cancer recurrence risk (RR 0.6); a prospective analysis of 289 growth hormone–deficient adults who, after 5 years of growth hormone therapy, showed lower risk of malignancy (RR 0.25) and decreased risk of myocardial infarction (RR 0.19) and early mortality (RR 0.22) compared with the untreated group.
In 2001, the consensus statement by the Growth Hormone Research Society noted that the data demonstrate that the concern for increasing the risk of cancer with the use of growth hormone is unfounded:
The current labeling for GH [growth hormone] states that active malignancy is a contraindication of GH treatment. There are, however, no data to support this labeling. Current knowledge does not warrant additional warning about cancer risk on the product label.
Supraphysiologic doses of growth hormone are shown to antagonize the effects of insulin. While short-term studies using large doses of growth hormone may potentially worsen insulin resistance, low physiologic doses of growth hormone have demonstrated improvement in insulin resistance and decreased risk of diabetes. If treatment is contemplated, low physiologic doses should be used to keep IGF-1 in the upper limit of normal. In conclusion, aging adults have a relative deficiency of growth hormone and supplementation with growth hormone may be of significant benefit. A clinical diagnosis of growth hormone deficiency can be made with support of low-normal IGF-1 levels alone. Although no long-term studies have assessed side effects with low physiologic doses of growth hormone supplementation in somatopause, the studies we reviewed above have confirmed that low doses, titrated to keep IGF-1 levels in the upper limit of normal, are safe, well tolerated, and associated with a plethora of clinical benefits.
Treatment with growth hormone is presently limited to an affluent and highly motivated population. Cost and risk/benefit ratio over time must be taken into consideration. As our patients age, the challenge of maintaining quality of life for them becomes more difficult and must be considered in the design of future studies. For supplementation with growth hormone to become a first-line therapeutic option in the aging population, additional and more extensive randomized trials that evaluate results of growth hormone treatment in age-related deficiency must be undertaken, and cost factors must be addressed.
In summary, we believe the well-informed use of hormones in wellness and disease prevention will result in symptomatic improvement and should be considered an integral part in the armamentarium of options we offer our patients. Definitions and testing of hormone deficiency that apply to illnesses do not apply to wellness and prevention and need to be reevaluated while we develop new treatment paradigms to best care for our patients. With the limited amount of research focused primarily on the areas of wellness and prevention, we must acknowledge the infinite number of variables that confound the results of every study. Ultimately we must focus on the individual patient and his or her need and that is the area where the doctor–patient relationship is of utmost importance and is the key to true prevention and wellness.