Global awareness of the signs and symptoms of low testosterone have increased dramatically over the last 20 years. With this increased awareness has come an increase in testosterone prescriptions for males of all ages, including patients in their 20’s and 30’s, when testosterone deficiency is far less likely.

While the guidelines advise presence of typical symptoms as well as 2-3 confirmatory low levels of testosterone, many clinicians are using symptoms alone to diagnose and initiate treatment. A practice that has significant potential for harm, as well as increased risks of infertility, none of which is being discussed with patients.

Low testosterone in males can contribute to depression, low libido, fatigue, loss of muscle mass and general malaise. While testosterone replacement is a safe and well-studied treatment, it should only be prescribed in men with a confirmed deficiency, and a proper discussion of risks and benefits. Best practice includes appropriate lab and clinical follow up to ensure potential side effects are minimized and when present, recognized and managed in a timely manner.

What is normal testosterone physiology in a male?

Testosterone is responsible for several important functions in healthy adult males including spermatogenesis, initiation of red blood cell production, enhancing libido, supporting bone and muscle health, and encouraging overall wellbeing.

According to the Endocrine Society, approximately 35% of men older than 45 years of age and 30-50% of men with obesity or type 2 diabetes have low testosterone, or hypogonadism.

Hypogonadism is defined by the presence of classic symptoms and concomitant lab values that demonstrate lower than normal testosterone levels compared to age matched individuals.

Symptoms of low testosterone include:

1. Decrease in energy
2. Decrease in libido
3. Infertility
4. Decrease in muscle mass or trouble gaining muscle mass despite adequate stimulus
5. Low bone mass/osteoporosis in a young male
6. Decreased vigor
7. Depressed mood
8. Gynecomastia (male breast enlargement)
9. Decreased body hair
10. Hot flashes

Men may present with any of the symptoms above and testing should be considered in males with typical symptoms and especially in those with symptoms plus risk factors such as type 2 diabetes and or obesity.

Conditions that should prompt testosterone testing:

1. Medications that affect testosterone production, such as high-dose glucocorticoids for a prolonged period and sustained-release opioids
2. Human immunodeficiency virus (HIV)-associated weight loss
3. End-stage kidney disease and maintenance hemodialysis
4. Moderate to severe chronic obstructive lung disease
5. Infertility
6.  Osteoporosis or low-trauma fracture, especially in a young man
7.  Type 2 diabetes mellitus

How is hypogonadism diagnosed?

The diagnosis of hypogonadism is made by measuring a fasting (food can further decrease your testosterone level) testosterone level drawn between 8 and 10am. If the initial level is low (this is age dependent) than a repeat measurement should be done to confirm the diagnosis, you may consider a 3^rd repeat in older men.

A testosterone measurement less than 300ng/dL is considered low, though the cutoff may be even lower in older men, as testosterone levels tend to decline with age. We won’t be covering testosterone replacement in older males today.

What is causing low testosterone? What is the difference between primary and secondary hypogonadism?

There are 2 main causes of low testosterone:

1. Dysfunction at the level of the gonads (testicles)
2. Dysfunction at the pituitary or hypothalamus (parts of the brain that regulate the gonadal production of testosterone)

The production of male hormones, like many other endocrine systems, works on a negative feedback loop- when testosterone levels are high, the brain tells the body to produce less hormones by decreasing the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Conversely, when testosterone levels are low, LH and FSH levels are increased to encourage the production of testosterone.

When we confirm an initial low testosterone measurement, we then add LH and FSH to help us determine whether you have primary (testicular) or secondary (pituitary/hypothalamus) hypogonadism.

If testosterone is low and LH and FSH are high- the diagnosis is primary hypogonadism (something is not working correctly in the testis)

If testosterone is low and LH and FSH are also low- the diagnosis is secondary hypogonadism (something is not working correctly at the level of the pituitary or hypothalamus)

Both conditions will respond to testosterone replacement, the distinction is more important when we are looking at causes for male infertility.

Primary Vs Secondary Hypogonadism – My Endo Consult

What are the treatment options?

Treatment options include buccal, nasal, subdermal, transdermal and intramuscular testosterone (IM) formulations. Most often in the US males are treated with transdermal and IM preparations.

Formulation	Dosing frequency	Pharmacology	Advantages	Disadvantages	T monitoring
Buccal	1 tablet, 2x daily- applied to the gums	Level peaks at 10-12 hrs, and level drops 2-4 hrs after cessation	Mimics circadian release of T, quickly metabolized	Gum irritation, twice daily dosing	Immediately  before or after a dose
Nasal	1 spray per nostril, 3x daily	Level peaks in 40 mins, ½ life is 10-100 mins	Non-invasive, no risk of transfer	Nasal irritation, nosebleeds 3x daily dosing	Periodically, 1 month after initiation
Subdermal	Implanted every 3-6 months	Level peaks around 8 hrs and ½ life is 1 hr	Infrequent dosing, higher compliance	Surgical procedure, infection risk at insertion site	At the end of the dosing interval
Transdermal	Patch or gel/foam applied once daily	Varies by product- peak anywhere from a few hours to 24 hours, consistent delivery over 24 hrs	Mimics circadian release of T, easy application (patch) Easy application, non-invasive (patch, gels, foams)	Need to change patch site daily, cannot repeat for 7 days (patch), high risk for skin irritation, blistering   Risk of transfer for others (gels/foams)	Patch: 2 weeks after initiation, 3-12 hours after patch application   Gels: 2 and 4 weeks after starting
Intramuscular	Injection every 1-4 weeks	Varies by product- peak is usually 72hrs-7 days, subtherapeutic by the end of the injection	Less frequent dosing than gels/patches	Fluctuations in mood/libido	Generally 1 week after dosing

How do you know if the dose is therapeutic?

Testosterone levels should be monitored 8-12 weeks after initiation of therapy, and 8-12 weeks after dosage adjustments. Once levels have stabilized, they can be checked every 6-12 months. If the patient has primary hypogonadism- LH levels can be measured as well- if the testosterone dosing is adequate, this should also normalize. Additionally, patients should experience resolution/improvement of their presenting symptoms.

Ideally males should be treated to a testosterone level between 400-700ng/dL

What do you need to monitor while on testosterone?

H&H: At baseline prior to initiating therapy patients should have a hemoglobin (red blood cell) and hematocrit (percentage of red blood cells)- since testosterone stimulates red blood cell production it is important to know baseline values, should also be measured 3 months after initiating treatment and then at least annually. If levels are above normal- the testosterone dosage should be reduced and the patient should be evaluated for hypoxia and sleep apnea with correction of underlying conditions, if none are identified, and the testosterone level is in the low normal range, phlebotomy can be considered.

PSA: Prostate specific antigen level- should be measured at baseline, then three months after treatment and again, annually- if there is an increase above 4ng/ml OR an absolute increase of 1.4ng/ml in one year, a urology referral should be initiated.

What are consequences of overreplacement?

When it comes to testosterone replacement, more is not always better.  Higher levels of testosterone can result in:

-Elevated hemoglobin and hematocrit

-Elevated PSA (prostate specific antigen)

-Worsening in BPH (prostate hypertrophy/enlargement)

–Increase in estrogen (excess testosterone is converted to estrogen in adipose tissue (this should be monitored and may be treated with aromatase inhibitors (AI) and selective estrogen receptor modulators (SERMs)- beyond the scope of this article- but certainly something to discuss with your treating physician.

A brief aside: since we’ve already mentioned estrogen, we should probably go over its role in normal male physiology. Estrogen is involved in regulating erectile function, spermatogenesis and libido. The importance here is balance– excess estrogen in males can cause gynecomastia, erectile dysfunction, infertility, slowed growth, fatigue, loss of muscle mass, loss of body hair and poor focus.

How does testosterone replacement impact fertility?

While it is a highly effective treatment for low testosterone, replacement does inhibit intratesticular (inside the testicle) testosterone production which is an absolute requirement for spermatogenesis.

Fortunately, for many men, cessation of testosterone therapy will result in gradual resumption of spermatogenesis (generally 3-4 months after cessation of therapy)

Options to help increase testosterone without affecting spermatogenesis include:

clomiphene citrate: This is a SERM medication that blocks negative feedback to the brain and increases LH secretion, which increases testosterone production.

Testosterone plus clomiphene citrate: The combination ensures adequate testosterone levels while supporting spermatogenesis

HCG: this is an FDA approved medication- HCG is an LH analog that stimulates testosterone production

Are there any natural ways to optimize testosterone levels?

1. Get enough sleep- important for optimal hormone functioning and secretion- testosterone secretion is dependent on our circadian rhythm
2. Maintain a healthy weight- excess adiposity is a leading cause of lowered testosterone levels (even more so than age)
3. Weightlifting or HIIT workouts- both are known to boost testosterone levels
4. Minimize alcohol consumption- excessive alcohol consumption can damage Leydig cells in the testis (cells responsible for making testosterone) as well as disrupting the HPA axis which secretes the hormones that stimulate testosterone production (LH, FSH and GnRH)
5. Consume foods high in resveratrol (like red grapes)- resveratrol may increase the conversion of cholesterol into testosterone, and act as an aromatase inhibitor, thereby decreasing estrogen levels (at least that’s what happened in animal studies)
6. Get enough vitamin D in your diet- vitamin D plays a role in sperm motility and testosterone creation
7. Garlic (allicin)- stimulates the release of LH (which stimulates testosterone production)
8. Consume honey- stimulates the release of LH which increases testosterone) as well as preventing oxidative stress to the Leydig cells

Bottom line: hypogonadism, or testosterone deficiency, is a common condition amongst males. Left untreated testosterone deficiency can significantly compromise quality of life for affected individuals and cause downstream pathology. Unfortunately, it is often mismanaged, increasing the risk of adverse events and even resulting in irreversible infertility. Not all treating providers are equally educated, and it is important to do your research! If you aren’t given a full risk/benefit profile with your personal medical history taken into consideration, you probably need to find another provider.

I hope this information has been helpful!

Sincerely,
Corsano MD- Your friendly neighborhood PCP

Testosterone Deficiency Guideline – American Urological Association
Testosterone deficiency in adults and corresponding treatment patterns across the globe – PMC
Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use – PMC
Exogenous testosterone: a preventable cause of male infertility – PMC
High Estrogen in Men After Injectable Testosterone Therapy: The Low T Experience – Robert S. Tan, Kelly R. Cook, William G. Reilly, 2015
uptodate: Testosterone treatment of male hypogonadism
uptodate: Clinical features and diagnosis of male hypogonadism