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Midlife Transitions—The Integrative Preventive Medicine Approach to the Evaluation and Management of Menopause and Andropause 

Midlife Transitions—The Integrative Preventive Medicine Approach to the Evaluation and Management of Menopause and Andropause
Chapter:
Midlife Transitions—The Integrative Preventive Medicine Approach to the Evaluation and Management of Menopause and Andropause
Author(s):

Cynthia Geyer

and Steven Brewer

DOI:
10.1093/med/9780190241254.003.0020
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date: 27 November 2020

Menopause

Menopause refers to a narrow window of time, 12 months after the normal cessation of a woman’s menses. The average age for menopause is 51, although the age of natural menopause can range from 40 to 55. The perimenopause, or menopause transition, can begin as early as a decade before a woman’s last menstrual period; average onset is 6–8 years prior.1 The early transition is characterized by wider fluctuations in estrogen production along with less consistent ovulation and progesterone production; eventually shifting to low levels of both hormones, usually with longer intervals between menses, until the final menstrual period. Symptoms can range from relatively few at one end of the spectrum to significant hot flashes, night sweats, disrupted sleep, heavy irregular periods, and decreased mood, which can negatively impact a woman’s quality of life. Historically much of the conversation between women and their healthcare providers has centered on the discussion of whether they should take hormone replacement therapy (HRT), now commonly called hormone therapy (HT).

The following vignette illustrates common questions a woman in midlife may bring to her integrative and preventive medicine practitioner. A 49-year-old woman comes in for your opinion on HRT. Her periods have become more irregular, and she is noticing some hot flashes 4–5 times a day, which she describes as mild but noticeable. She is also waking up 2–3 times a night with night sweats, and is usually able to go back to sleep. However, she feels more fatigue and irritability in the daytime. She is concerned about HRT because her mother had breast cancer at 75. She read that bioidentical hormones are a more natural, safe approach, but she has received conflicting advice about whether she should take HT from her primary care physician and her gynecologist. She is seeking additional recommendations from you.

The pendulum of professional opinion has swung widely from recommending HT for most women, after the observational Nurses Health Initiative linked HT to lower risk of heart disease and osteoporosis, to strongly recommending against it after the randomized prospective Women’s Health Initiative (WHI) found paradoxically higher cardiac events in addition to higher rates of breast cancer in women assigned to take HT.2 Roughly two-thirds of the women in the WHI were 63 or older, representing a group likely to be physiologically different from most women entering menopause. This may have contributed to some of the negative findings related to cardiovascular risk: More recent subset analysis has found that outcomes differed by age. Key points that came from reanalysis:3

  1. 1. In women who started HT before the age of 70 or within 20 years of their last menstrual period, no increase in cardiovascular disease was seen.

  2. 2. In women who had no uterus and used conjugated equine estrogens only (ET), starting between the ages of 50 and 59, a trend toward fewer cardiovascular events was seen. Less coronary calcium was also seen.

  3. 3. Overall mortality was decreased in younger women on ET only.

  4. 4. Newer research adds more evidence that the form of HT used, the route of administration, and the timing of initiation in relation to a woman’s last menstrual period all influence the potential benefit versus harm, particularly in regard to cardiovascular and thrombotic risk.4,5,6 A recent observational study found that thrombotic risk from oral estradiol was much lower than from oral conjugated equine estrogens,7 and no increased thrombotic risk was seen with either transdermal or intravaginal preparations.8 Both the MESA and the ELITE trials add support for the timing hypothesis: earlier HT was associated with slower coronary calcium buildup and less carotid plaque buildup, respectively.9,10

As clinicians work with women in the menopause transition it is important to recognize the interplay among many different hormones beyond estrogen and progesterone with regard to symptoms. Insulin dysregulation,11 subclinical thyroid disorders,12 declining melatonin,13,14 and production of catecholamines and cortisol in response to stress15,16 all influence symptoms of the menopause transition and also play a role with the increased risk of diabetes, heart disease, and breast cancer in the post menopause. Disrupted sleep and increasing prevalence of sleep apnea may exacerbate weight gain, insulin resistance, and mood changes.17 Emerging evidence implicates the gut microbiome18,19 and exposure to endocrine-disrupting chemicals20,21 as additional modulators of many aspects of the hormonal environment, particularly related to insulin and estrogen. Perhaps most significantly, the timing of menopause often coincides with many other life transitions for women. Children may be leaving home; women may be rethinking their long-term career or partner; they may grieve the loss of their parents or be dealing with their parents’ health issues and functional decline; more peers and friends in their age group are facing cancer, heart disease, and other serious health concerns. A truly integrative approach takes all these factors into consideration in the partnership with each woman about the best individualized approach for her to reduce her symptoms, decide if hormones are right for her, and incorporate the lifestyle strategies that will not only reduce her risk of heart disease, osteoporosis, and breast cancer but also support her thriving in the post menopause.

These are key areas to explore with women in the conversation around the menopause transition (in addition to past medical and family history):

  1. 1. Symptoms such as hot flashes and night sweats: how often, how disruptive or not, any known triggers

  2. 2. Sleep: changes in ability to fall asleep/stay asleep; impact of night sweats on sleep; presence of snoring; daytime fatigue (see chapter 19)

  3. 3. Mood: irritability, weepiness, depression, feelings of helplessness, hopelessness; history of premenstrual or postpartum mood changes

  4. 4. Weight history and any recent changes

  5. 5. Libido: changes in sex drive, vaginal dryness, pain with vaginal penetration, decreased ability to attain orgasm; if still menstruating and sexually active with a male partner, use and type of contraception, satisfaction with method

  6. 6. If in a relationship: emotional and physical safety, shared interests, emotional connection, partner’s physical and mental health

  7. 7. Community: who are her supports?

  8. 8. Concerns/fears/joys; thoughts and attitudes around aging

  9. 9. Thoughts/preferences/level of knowledge around HT

The preceding chapters have given excellent reviews on the integrative and preventive medicine approach to common clinical problems. What may be unique about women in the menopause transition is that for many, although their symptoms may get their attention, it may also be the first time they have started to think about aging and their risk of these common conditions. The menopause transition thus provides an opportune time to establish benchmarks in health and prioritize together the best lifestyle changes to help manage symptoms and lower risk of disease.

Helpful benchmarks:

  1. 1. Anthropometrics: height, weight, waist circumference, waist:hip ratio

  2. 2. Blood pressure

  3. 3. Fitness level—estimated or measured

  4. 4. Mammogram and breast tissue density

  5. 5. Bone density

  6. 6. Assessment of fat free mass, percent body fat and distribution (by caliper, bioimpedence analysis [BIA], DEXA scan), particularly for women with a lower BMI but elevated waist:hip ratio

  7. 7. Bone turnover/bone formation

  8. 8. Complete lipid profile with LDL and HDL size, remnant lipoproteins

  9. 9. hsCRP

  10. 10. Fasting glucose, insulin, (calculated HOMA-IR), Hgb A1c

  11. 11. TSH, free T4, free T3

It is also important for practitioners to understand their own opinions about HT and be open about any general biases they may have. In the wake of uncertainty, mixed study results and shifting professional guidelines about the long-term risks and benefits of HT, some healthcare practitioners have aligned on the side of generally recommending against HT while others have broadly recommended it for most of their patients. Being open about your opinions and also willing to explore the mindset of your patients fosters a relationship that allows a mutual exploration of the best approach for that particular person at a given point in time, consistent with her symptoms, concerns, goals, and attitudes. Establishing an open and respectful dialogue sets the stage for checking back in and modifying the approach over time as symptoms and goals change (and as new research about HT is published).

The potential pros and cons of HT have been extensively reviewed elsewhere. Hormone therapy remains the most effective treatment for the vasomotor symptoms of menopause, and also shows benefit for mood22 and sleep. For women who do not have existing coronary artery disease, HT is likely to be safe (and may even lower risk) from a cardiovascular standpoint when initiated within a 6-year window from the last menstrual period. Because transdermal estrogens are less likely to have a negative impact on raising C-reactive protein (CRP), blood pressure, clotting factors and triglycerides, this is my preferred route of administration. Transdermal preparations are available as patches, creams, gels, and a mist.

“Bioidentical” is a term that has generated confusion for patients and practitioners. In its strictest definition, it refers to hormones that are identical on a molecular level to those endogenously produced (such as estradiol [E2], progesterone, and testosterone).23 It is generally used in reference to compounded forms of sex hormones, which commonly use a combination of 70% estriol (E3) and 30% estradiol (E2). Standardized pharmaceutical preparations of bioidentical hormones (E2 and progesterone) are also available in a wide range of doses. Although the compounded versions are often marketed as “natural and safe,” they are not regulated by the Food and Drug Administration and there has been a lack of studies looking at long-term outcomes. Estriol, the weakest of the three naturally occurring estrogens, has been touted as potentially providing benefits of estrogen without the risk of breast cancer. However, in human breast cancer cell lines, low levels of estriol were able to trigger a robust estrogenic response.24 It is important for practitioners and their patients to recognize that even compounded HT is still HT: the same risk:benefit conversation is indicated.

In women with an intact uterus, unopposed estrogen is associated with an increased risk of hyperplasia of the uterine lining and with uterine cancer. Administering progestins mitigates that risk,25 but progestins may also differentially affect cardiovascular risk factors, breast cancer risk,26,27 and mood. Medroxyprogesterone, as opposed to progesterone, adversely affects endothelial function, lipids, and insulin sensitivity. In the WHI, higher rates of breast cancer were seen with combined conjugated equine estrogens (CEE) and medroxyprogesterone but not with unopposed CEE;28 results from a prospective French cohort study named E3N did not find an elevation in breast cancer risk for women using estrogen and progesterone.29 Both forms of progestins may negatively impact mood in susceptible women. Several regimens have been used to try and decrease total progesterone exposure while still protecting the lining of the uterus. Cycling progesterone, taking it the first 12 days of the month, is one option. Another is vaginal progesterone: In the recently reported ELITE trial, a 4% progesterone gel was administered vaginally on the first 12 days of each 30-day time frame. Although not FDA approved, dosing the 4% progesterone gel twice weekly on the day of changing an estradiol patch may also be acceptable. Until more long-term studies are done confirming the uterine protection of this latter regime, annual surveillance with a transvaginal ultrasound to look at the thickness of the endometrial lining would be reasonable. In my practice working with women who decide to try HT and for whom it is not contraindicated, I usually start with a low-dose FDA-approved standardized estradiol patch twice weekly and either nightly progesterone 100 mg (taking advantage of the potential soporific effects if there are sleep concerns)30 or a 200-mg dose of progesterone orally on days 1–12 of 30 days. If a woman has a history of depression, premenstrual and/or postpartum depression, or does not tolerate the progesterone, vaginal administration of 200-mg progesterone or 4% progesterone gel can be done on days 1–12.

One of the biggest concerns with long-term HT is the potential for increased risk of breast cancer.31 Understanding a woman’s baseline risk of breast cancer is critical; one online risk calculator, based on the original Gail model and developed by the National Cancer Institute and the NSPI, is available at cancer.gov. Questions include age, ethnicity, onset of menarche, age of first live birth, prior history of breast cancer or chest radiation, known BRCA or other genetic risk, number of first-degree relatives with breast cancer, and history of breast biopsies/atypical hyperplasia. The Rosner-Colditz model32 adds BMI, alcohol intake, and additional reproductive factors to the Gail model. Newer risk-prediction models are being developed that include common single nucleotide polymorphisms (SNPs) associated with elevated risk of breast cancer.33 Other factors that increase risk of breast cancer include weight gain after menopause,34 the presence of dense breast tissue,35 high bone density,36,37 insulin resistance,38 and working night shifts (possibly due to lower melatonin).39,40 Although less clear from the literature, certain dietary factors (low intake of fiber, omega-3’s, fruits, and vegetables)41,42 and exposure to persistent organic pollutants (POPs) or endocrine disrupting chemicals (EDCs)43 may also influence risk. The higher the number of risk factors, the more a practitioner may elect to recommend against long-term HT (usually defined as >5 years).

If a woman chooses to try HT, addressing other potentially modifiable risk factors for breast cancer is crucial. The combination of HT and alcohol intake significantly increases risk.44 Proposed mechanisms include alcohol’s effect on decreasing estrogen metabolism, resulting in higher circulating estrogen in the bloodstream;45 and increased needs for folic acid, a key cofactor for estrogen detoxification and DNA repair.46,47 Incorporating regular physical activity; adopting a dietary pattern high in fiber, fruits and vegetables, and omega-3 fatty acids; and even reducing evening calorie intake and prolonging the overnight fasting interval may have beneficial effects on lowering insulin and insulin resistance, reducing inflammatory adipocytokines, supporting a more diverse gut microbiome, and increasing estrogen excretion.48,49,50,51,52

In addition to the association between weight gain and insulin resistance in the menopause transition with both higher rates of cardiovascular disease and breast cancer,53 a deeper understanding of the relationship between insulin and menopausal symptoms is emerging.

  1. 1. Higher weight is associated with more vasomotor symptoms, and in turn a higher frequency of hot flashes is associated with higher glucose levels and insulin resistance, as estimated by the homeostasis model assessment of insulin resistance (HOMA-IR).54,55

  2. 2. In the WHI, weight loss significantly reduced hot flashes in women not on HT.56 A more recent pilot study found that a behavioral approach to weight loss was effective in reducing hot flashes, and hot flash reduction was a major motivator to lose weight in 74% of the women studied.57

  3. 3. Weight gain adversely affects lipids, blood pressure, diabetes, and cardiovascular risk and can contribute to sleep apnea, which in turn exacerbates weight gain, insulin resistance, and dyslipidemia.

  4. 4. Arguably, addressing insulin resistance may be the most important hormonal modulation for women in an effort to improve symptoms and health outcomes in the transition and the postmenopausal years.

Women’s desire for, and their ability to comfortably engage in, sexual activity may be impacted by the physical, emotional, and other changes of menopause. Many studies suggest that estrogen, not testosterone, has a larger impact on sexual desire.58,59 Thinning of the vaginal epithelium and decreased lubrication may not occur until several years after the last menstrual period and can contribute to painful penetration. Those tissue changes along with alterations in vaginal flora and increase in vaginal pH may increase susceptibility to postcoital urinary tract or yeast infections. Attitudes about aging,60 disrupted sleep and decreased energy, being uncomfortable with a changing body, and feeling emotionally distant from a partner61 all impact a women’s sexual desire. Vaginal estrogen is extremely effective in improving atrophy,62 favorably impacting the vaginal microbiome,63 and reducing urinary tract infections.64 However, some women will absorb enough to elevate serum levels of estradiol, which may be a concern in women with a history of breast cancer.65 A recent study found that daily intravaginal dehydroepiandrosterone (DHEA) 0.5% (6.5 mg) for 12 weeks resulted in an 86%–121% improvement in vaginal secretions along with improved integrity, color, and surface thickness of vaginal epithelium. Significant reduction in vaginal dryness and pain with sexual activity were also seen compared to placebo. Serum levels of DHEA and its metabolites, including testosterone, estradiol, and estrone, remained within normal postmenopausal limits. This appears to be an effective and safe option for treatment and management of vulvovaginal atrophy.66 Vaginal DHEA received FDA approval for this indication in November 2016. In addition to addressing physiologic changes that can impact a woman’s desire for and comfort with sexual activity, it is equally important to address relationship concerns and attitudes about aging. The American Academy of Sexuality Educators, Counselors and Therapists (www.aasect.org) is a resource for finding certified professionals for referral if indicated.

There are several nonhormonal modalities that may have benefit for relief of bothersome symptoms. Unfortunately, assessing efficacy of many commonly used therapies is hindered by lack of good-quality studies. It is important to recognize that “lack of evidence to support” a modality is not the same as “proof of ineffectiveness.” That awareness needs to be balanced with the potential for harm. A comprehensive review of the comparative effectiveness and strength of evidence, along with potential risks, behind hormonal, nonhormonal pharmacologic, and supplemental and botanical therapies for menopausal symptoms was published by the Agency for Healthcare Research and Quality in March 2015, available at healthcare.ahrq.gov. In addition to HT, high-strength evidence shows the effectiveness of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) on vasomotor symptoms, anxiety and depression, and overall quality of life. The North American Menopause Society’s (NAMS) position paper published the same year also cited level I evidence supporting the use of paroxetine salt,67 currently the only FDA-approved nonhormonal treatment, for symptom relief.

The AHRQ’s review found low-level evidence for the effectiveness of dietary or supplemental isoflavones. A more recent meta-analysis concluded that phytoestrogen supplementation, dietary and supplemental soy isoflavones (primarily genistein and daidzein), were moderately effective in reducing hot flashes and vaginal dryness, but not night sweats.68 For a trial of soy isoflavone supplementation, a dose of 50 mg/d or higher should be used. A supplement containing s-equol (level II evidence according to NAMS) may be effective if women do not respond, since some women lack the gut bacteria that convert daidzein to s-equol. For red clover isoflavones, the usual dose is 80 mg/d.69 Because of the phytoestrogenic effect of isoflavones, concerns have been raised about their safety in women with a history of breast cancer. A meta-analysis in 2013 concluded that isoflavone intakes in the doses typically used do not appear harmful and may even be associated with lower risk of breast cancer recurrence and mortality.70

Both reviews concluded that neither black cohosh nor dong quai, commonly used herbs, showed evidence for beneficial results. Limited evidence has shown improvements in symptoms using ERr73171,72 (an extract from Rheum rhaponticum) and pycnogenol73 (extract from pine bark). The dose for pycnogenol ranges from 30 to 100 mg/d. In higher doses (150 mg/d) pycnogenol has also shown beneficial effects in blood glucose, lipids, waist circumference, oxidative stress, and endothelial function.74

The NAMs position paper also cited level I evidence for cognitive-behavioral therapy and hypnotherapy as effective modalities for symptom relief. Mindfulness-based stress reduction was “recommended with caution,” citing a need for additional studies; while acupuncture was not recommended. A more recent study found that telephone-based cognitive-behavioral therapy for insomnia was effective in improving sleep quality in women with vasomotor symptoms.75 The Cochrane review found low-level evidence of benefit with acupuncture compared to placebo but not compared to sham acupuncture.76 A more recent study of 190 women with breast cancer found significantly lower hot flash scores and improved quality of life in the group who received 10 acupuncture treatments plus an informational booklet on self-care compared to the women who only received the booklet. Differences remained significant 3 and 6 months after treatment.77 Despite these conflicting recommendations, the low risk and possible effectiveness of acupuncture makes it a reasonable treatment for women to try, especially if HT is contraindicated.

Muscle mass begins to decrease in the 4th decade, and there is accelerated bone loss in the late menopause transition and the first years of the post menopause. Analysis of the Nationwide Inpatient Sample (NIS) between 2000 and 2011 found that for women age 55 and older, more were hospitalized for osteoporotic fractures than for myocardial infarction, stroke, and breast cancer, highlighting the significant impact bone loss has on healthcare costs and morbidity.78 Hormone therapy can prevent the rapid phase of bone loss associated with the menopause transition, but the bone loss resumes upon discontinuation of HT. A preventive approach to minimize muscle and bone loss includes ensuring adequate dietary protein, calcium, magnesium, and vitamin D.79,80,81,82 Although there is debate about the optimal level of vitamin D for bone health, maintaining levels in the 30–40 ng/mL range is a reasonable target, based on National Health and Nutrition Examination Survey (NHANES) data.83 Higher adherence to a Mediterranean dietary pattern was associated with a 20% relative risk decrease in hip fractures and improved skeletal muscle mass and power.84,85 Vitamin K2, produced by intestinal bacteria from vitamin K1 (present in dark leafy greens), may have a unique role in both reducing vascular calcification and improving bone mineral density by reducing undercarboxylated osteocalcin and promoting osteoblast differentiation.86,87,88,89,90 Natto, a fermented soy product, provides the richest dietary source of vitamin K2, which is also found in aged and curd cheeses. Doses used in supplementation range from 45 to 100 μ‎g daily. A combination of low-impact exercise and resistance training may both improve bone density and have other benefits related to reducing fracture risk: improved strength, maintenance of muscle mass, improved stability and balance, and reduction of falls.91 A new bone balance index (BBI) using the ratio of bone turnover (measured by urinary N-telopeptide) to bone formation (serum osteocalcin) was found to predict women at risk for a faster decline in lumbosacral spine bone density and may prove to be a useful tool to identify women who need more intensive treatment and follow-up.92 The strongest correlate of a more favorable BBI was a high BMI. On the other hand, since high bone density may predict higher than average risk of breast cancer, it becomes part of the risk:benefit equation in deciding about HT.

Regardless of whether a woman’s initial decision is to try HT or to try alternative approaches to manage symptoms, encourage follow-up after a given period of time, such as 3–6 months, to review efficacy and side effects. If troublesome symptoms persist and HT is not desired or is contraindicated, a trial of an SSRI or SNRI may be offered. For women on HT whose symptoms have not responded, measuring an estradiol level may be helpful. If the level is extremely low, a higher dose of estradiol is reasonable. If the level is 40–100, efforts should be made to look for other contributors to symptoms if not already done. Reinforcement of exercise, stress reduction practices, quality and quantity of sleep, and a whole-foods diet can be done at each follow-up.

In summary, the menopause transition is a normal phase of a woman’s life and there is tremendous variability in different women’s experiences. Honoring the other life transitions that may coincide with changing hormones; “normalizing” the experience; framing it as an opportunity to reassess stress levels, dietary patterns, self-care, sleep habits, social support network, and quality of primary relationship; and individualizing recommendations with regular planned follow-up can ensure that women find what works best for them and reengage with the lifestyle strategies that contribute to lower risk of disease and improved quality of life through the menopause transition and beyond.

Andropause

Over the years much has been written about women’s decreased production of hormones that result in multiple symptoms that we call menopause. Women have spent the last 50 plus years trying to treat these symptoms of menopause by using various hormonal and herbal therapies. The consequence of using these treatments has not always been good. There has been a potential of developing breast and uterine cancer.

Men have thought menopause is a “disease” that only women need to worry about. The reality is that men also have the potential of having lower levels of sex hormones. This has loosely been called andropause or late-onset hypogonadism. With scientific advances we have improved our understanding on how the male hormone system works. Men and women both go through changes as they age. One big difference seen with men compared to women is that men generally have a more gradual onset of hormonal changes. Men may notice difference in their libido or in their general mood over months and years where women will often notice changes emotionally in weeks and sometimes days.

So what really is andropause or the male version of female menopause? It is defined as a decrease in serum concentration of a man’s testosterone level. The difference between female menopause and male andropause is that women generally have rather rapid loss of estrogen production from their ovaries. In men they generally have a more gradual decrease in their testosterone level or production of sperm as they age. The lower production of testosterone can cause many physical and emotional changes in the body.

Testosterone is responsible for the growth and development of the male reproductive system, but for these changes to take place, testosterone must first be converted to dihydrotestosterone. It is actually dihydrotestosterone that produces the male effects. During puberty with the higher production of testosterone and subsequently the higher level of dihydrotestosterone, the penis and testes increase in size. Testosterone also has an anabolic effect on the body. It increases muscle mass and promotes healthy bones by increasing bone density and mass. Other secondary sexual characteristics that are a result of increased testosterone production are facial, pubic, armpit, and chest hair.

There are basically two types of male andropause. The first is primary hypogonadism. This is where the problem is in the testes themselves. The levels of testosterone are decreased, and the production of sperm is often lower. It can be diagnosed by showing lower testosterone levels and a person’s leutenizing hormone (LH) and/or follicle stimulating hormone (FSH) are above normal. The LH and FSH are the pituitary hormones whose job is to stimulate the testes to make testosterone and sperm. With secondary hypogonadism the testosterone and sperm count are low and the LH and/or FSH are normal or low. In this case the pituitary hormones, LH and FSH, are not producing enough to stimulate the testes effectively. This can be the result of a brain injury or a mass effect on the pituitary gland like a pituitary tumor.

There are several kinds of physical changes that can occur with andropause. One of the first physical changes that can occur is a decreased ability to obtain a spontaneous erection. Other physical findings are smaller testes and penis, hot flashes, decreased bone density, lower muscle mass, and lower sperm count. Also there can be an overall decrease in body hair. A secondary effect of andropause can be an increase in a man’s percent body fat. With the loss of muscle mass that can occur with a decreased testosterone production, there is a decrease in caloric burn, which results in an increase in body fat.

There are psychological changes that can occur during andropause with lower testosterone levels. This first most obvious condition is a decrease in libido (sex drive). This can be such a gradual onset that men think that this is just a function of life and it is something to be expected. Other common psychological symptoms that men or their friends or significant others may notice is fatigue, depression, or a decreased ability to focus or concentrate.

There are various causes for decreased production of testosterone. Aging is the most common reason. As men age their testosterone production is lowered by 20% in their 60s, 30% in their 70s, and 50% in their 80s.93 Other causes of decreased testosterone production can be seen with men who have a chronic illness. Some examples of that are diabetes, obesity, autoimmune diseases, cancers, HIV infections, and chronic kidney and liver disease. There are acquired causes of decreased testosterone production. This is seen with a direct injury to either the testicles or pituitary gland, if the individual has had the mumps virus, if the person drinks excessive alcohol (alcohol can have a direct toxic effect), or if the man has had systemic chemo or radiation therapy.

Having erectile dysfunction is the first thing that most people equate with a low testosterone level. This is an inability to maintain an erection more than 75% of the time during a sexual encounter. Certainly, low testosterone can be one of the causes of erectile dysfunction, however it is important to know that there are reasons other than low testosterone that can cause erectile dysfunction. These causes must be ruled out before any consideration for the use of testosterone is made. This can be seen with damage to the nerves that are involved in the ability to obtain an erection. To have an erection a man must have a psychological increased desire for sex. This information is sent down to the spinal cord from the brain to the thoracic spine 11 to lumbar spine 2. From that region of the spinal cord, a nerve fiber sends a signal to the iliac arteries (the major arteries that supply blood to the legs) to redirect a significant amount of blood flow to the penis to obtain an erection. Neurologic disease anywhere along this nerve path can cause erectile dysfunction. Some of these common neurologic diseases to the nerves include multiple sclerosis, spinal cord trauma, urological surgical procedures like prostate surgery, and nerve compression injuries that can occur with prolonged cycling. There are other metabolic causes of nerve damage that are seen in diseases such as diabetes. So any injury to these nerves can decrease the ability to have an erection.

Other causes of erectile dysfunction are disease states that can decrease the blood flow to the penis such as atherosclerosis (hardening of the arteries). The men most commonly seen with this condition are men who have the risk factors for cardiovascular disease. Those risk factors are a history of smoking, elevated cholesterol, increased blood sugars, lack of exercise, and elevated inflammatory rate (determined by a high C-reactive protein blood test). One of the most common causes of erectile dysfunction is medication. There are multiple medications that can do this. Many of the antidepressants are associated with erectile dysfunction. One antidepressant group in particular is the SSRIs (selective serotonin reuptake inhibitors). The first drug in this group was Prozac. These antidepressants increase the neurotransmitter serotonin, which is often low in depressed individuals. These drugs are excellent drugs in treating depression, however they may have the unfortunate side effect of lowering the ability to obtain an erection. Another common group of drugs associated with erectile dysfunction are many of the antihypertensive (blood pressure) medications. Two common types are the diuretics (the water pills) like the thiazide diuretics and beta-blockers. Other drugs known to cause erectile dysfunction are certain medications called 5-alpha reductase inhibitors. These drugs block the conversion of testosterone to dihydrotestosterone. These drugs are used to treat enlarged prostates and hair loss. Examples of these are Dutasteride and Finasteride.

Andropause usually begins for men in their 50s. This is a big transitional time in a man’s life. This time is more than a decrease in testosterone, it has a lot of emotional transitions. Men at this age are often slowing down with their occupations and no longer are the young gunners trying to make a mark in their careers. It can be a difficult time emotionally because they are no longer the up-and-coming stars. Men have to emotionally deal with this slow-down phase, which can lead to a low level of depression. Because they cannot always accomplish what they have done in the past, men sometimes give up on many aspects in their lives, especially how they approach their fitness. In the past they may have focused on winning with their physical skills but now they may be having a hard time keeping up. For this reason they stop their physical fitness programs altogether. This causes weight gain and increases the risk of chronic ailments. Men need to acknowledge the physical limitations that occur with aging and andropause. They need to embrace and realize this is a fact of life then continue to exercise for the sake of maintaining health and not trying to keep up or compete with younger men. I have seen these phenomena over and over in my years of practicing medicine. Men constantly give up on their fitness program because they fall back in the pack and have slower and slower times with their exercise programs. They become so consumed about their inability to keep up that they completely give up on their health.

Another potential consequence of andropause is a loss of muscle mass. This is called sarcopenia. Testosterone is important in maintaining and the building up of muscles. With lower levels of testosterone there can be a 30% to 50% loss of muscle mass. This can lead to an inability to maintain balance, which can increase the risk of falls and subsequent injuries. These injuries can lead to more inactivity, which can lead to more loss of muscle mass and subsequently more falls and injuries. Men can acquiesce to this continual downward spiral with their health or they can fight it. One way to decrease muscle loss is to weight train. Resistance training (e.g., lifting weights) has been shown to not only slow down muscle loss but also actually increase muscle mass.94 In addition, as we get older, over the age of 65, eating higher protein levels (25 to 30 grams per meal) has also been shown to help prevent muscle loss.94

If a man has significant sarcopenia (despite the fact that they are doing resistance training and have increased their protein intake) and/or has some of the consequences of low testosterone (less than 300 ng/dL) such as erectile dysfunction, decreased libido, or depression, and there are no correctable causes of decreases in testosterone production, then there can be consideration for the usage of prescriptive testosterone. Through the care and guidance of a physician who is familiar with the uses of testosterone and prescribes it only after nonpharmacologic treatments have been pursued, it may be prescribed for that man.

The decision whether or not to use testosterone is based on the potential benefits versus possible side effects of the medication. In making this decision, the first thing to note is at the time of the writing of this chapter, there has been no evidence that the use of therapeutic testosterone causes prostate cancer. It has however been shown to accelerate the growth of a prostate cancer if it already exists. For that reason it is important to obtain a prostate-specific antigen (PSA) and have a digital rectal exam prior to the use of testosterone. If the PSA is elevated, then the man needs to be worked up to rule out prostate cancer before testosterone can be started. If prostate cancer is found initially then testosterone cannot be started.

The use of testosterone can stimulate the growth of normal prostatic tissue, which can increase the size of the prostate. This can be a problem if the prostate is already enlarged. Prostatic enlargement has the potential of closing off the man’s urinary flow. Symptoms associated with this are slow urinary stream, difficulty starting urination, urine retention, and getting up multiple times at night to urinate.

There are other potential physiologic problems associated with testosterone therapy. One is an increased production of red blood cells. This can lead to an increased risk for blood clots. Other problems are accelerated male pattern hair loss and the development of acne. Testosterone in addition can affect a person emotionally. It has been known to increase aggressive behavior. An important but controversial potential side effect of testosterone is cardiovascular disease. There have been conflicting reports on the risk of cardiovascular disease with the use of testosterone. Some studies have shown that if cardiovascular disease is already present, use of testosterone may cause progression of the disease.95 This has been disputed by a later study that did not show an increase of cardiovascular disease.96 The bottom line is that if a man has cardiovascular disease under the age of 65 or is over the age of 65 and is considering starting testosterone treatment, he should have a serious discussion with his doctor and possibly a consultation with a cardiologist prior to starting therapy.

Despite the potential side effects of testosterone, the benefits of testosterone may well be worth the risks. Summarizing, the possible benefits of testosterone include improved libido and possible reversal of erectile dysfunction. It may improve a man’s depressed mood and chronic fatigue. Muscle mass can increase, which in turn may help lower body fat by increasing a man’s metabolism and fitness capacity.

Andropause does not necessarily affect all men. It is not as inevitable as with women, who will all eventually have ovarian failure. If a man’s testosterone level does not drop significantly, there may be little symptoms that are commonly seen with andropause.

In integrative medicine the question arises as to whether or not there are any alternatives to testosterone for the fatigue, decreased libido, and erectile dysfunction. There are many herbal and supplements advertised and sold for male enhancement. The regulation of such therapies is loosely regulated because they are considered supplements. Some of these therapies have had limited effectiveness. In this country dietary supplements have been touted as substitutes for prescription testosterone. These dietary supplements have contained androstenedione, dehydroepiandrosterone, and androstenediol. They are precursors to the endogenous production of testosterone. (With the Anabolic Steroid Control Act of 2004, androstenedione is now a schedule III controlled substance and therefore it is regulated by the FDA and requires a prescription.) The efficacy and safety of these prohormones are not well established, but they are promoted to have the same androgenic effects on building muscle mass and strength as anabolic-androgenic steroids. Studies have demonstrated repeatedly that acute and long-term administration of these oral testosterone precursors does not effectively increase serum testosterone levels and fails to produce any significant changes in lean body mass, muscle strength, or performance improvement compared with placebo.97

There are medications for the specific treatment of erectile dysfunction with or without testosterone. The most commonly used drugs are the phosphodiesterase-5 enzyme inhibitors. Two examples are sildenafil (Viagra) and tadalafil (Cialis). They work by increasing the blood flow to the penis. They have been helpful for a lot of men over the years, however they have potential side effects. The most common is a headache. These drugs work by dilating blood vessels to improve blood flow to the penis. The problem is that these medications are not selective for the blood flow to the penis. It can dilate other blood vessels, most notably the cerebral arteries. When this happens it has the potential of causing a vascular headache.

Phosphodiesterase-5 enzyme inhibitors do not have to be the only solution to erectile dysfunction. An integrative approach is to try other nonpharmacological approaches first. It has been shown that nonpharmacological, nonsurgical therapies can reverse or improve erectile dysfunction in patients with organic, psychological, or mixed impairment. Among these therapies are lifestyle changes (losing weight, pelvic musculature strengthening, psychotherapy and/or psychoeducation, and improved sleep.98

If there is no obvious organic etiology for a man’s erectile dysfunction, such as a neurologic or vascular compromise, this is called psychogenic erectile dysfunction. Studies have shown that this form of erectile dysfunction can be resolved in about a third of the time. These patients are generally older, more often living with their partner, and more frequently resigned with the diagnosis of psychogenic erectile dysfunction than the patients who did not resolve their psychogenic erectile dysfunction. A nonchalant or cooperative female partner’s attitude to psychogenic erectile dysfunction improved the possibility of psychogenic erectile dysfunction resolution.99 It is important to note that other studies have shown that psychogenic erectile dysfunction has been associated with disrupted childhood attachments. This group often has earlier onset of erectile dysfunction, a lower likelihood of being married, and higher rate of performance anxiety.100

Overall, andropause is different from female menopause. The onset of andropause is generally slower than menopause, and in some men it may not even occur. The symptoms of andropause compared to menopause are generally less dramatic and the length of onset of symptoms can be years, versus months, as seen with menopause. It is a physiologic change in the body that men should not fear but be educated on and understand as they get older. Being knowledgeable of andropause allows a man to take action against the potential negative effects of andropause. This can be done by increasing resistance training to compensate for the loss of muscle mass with lower testosterone production. They can also maintain a healthy lifestyle that may help compensate for loss of testosterone by exercising regularly (a minimum of 30 minutes a day more days than not), eating a diet low in animal fats and high in fruits and vegetables, learning to control stress and maintaining a healthy weight. Finally, if men do these healthy lifestyle changes and still have significant symptoms of andropause, they can discuss with their doctor the potential use of hormone replacement therapy.

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