Andropause: Male Hormonal System

• Pamela W. Smith, M.D., MPH, MS, Copyright 2024

Objectives

• Understand the physiology and biochemistry of the male hormonal system
• Learn the definition of primary and secondary hypogonadism
• Know the signs and symptoms of andropause
• Explore the functions of testosterone in the body
• Study the role estrogen has in the male
• Examine the main reasons for hormone replacement therapy in men
• Review the contraindications to testosterone replacement
• Explore the possible side effects of testosterone replacement

Andropause

• Andropause is an absolute or relative insufficiency of testosterone or its metabolites in relation to the needs of an individual at a specific time

Late-Onset Hypogonadism

• The term 'male menopause' was first used in 1944 to describe various complaints of aging men, mirroring climacteric symptoms in women
• This syndrome carries names, including male menopause or climacterium, andropause, and partial androgen deficiency of the ageing male (PADAM)
• The most common term now used is late-onset hypogonadism (LOH)

Prevalence of Hypogonadism

• 30% to 60% of men in their 70s are hypogonadal

Levels of Testosterone

• Testosterone levels decline with aging at 1% per year; this decline is more pronounced in free testosterone levels due to sex hormone binding globulin (SHBG) alterations
• Half of healthy men between 50-70 years have a testosterone level below the lowest level seen in healthy men who are 20-40 years of age
• The Massachusetts Male Aging Study showed that a 30-year decline in total testosterone in men averaged 48% and a decline in free testosterone of 85%
• Seasonal variations exist in levels of testosterone with peak levels found in the summer and early fall and lower levels in the winter and early spring

Healthy Male Daily Hormone Production

• Cortisol: 20-30 mgs/day
• Testosterone: 5-6 mgs/day
• Androstenedione: 3 mgs/day
• DHT: 0.300 mgs/day
• Estrone: 0.066 mgs/day
• Estradiol: 0.045 mgs/day
• DHEAS: 50 mgs/day
• DHEA: 15 mgs/day

Primary vs. Secondary Hypogonadism

• Primary hypogonadism results from malfunction at the level of the testes due to a genetic cause, injury, inflammation, or infection
• Hypothalamic and/or pituitary failure leads to secondary hypogonadism, most often as a result of genetic defects, neoplasm, or infiltrative disorders
• To determine whether a patient has primary or secondary hypogonadism, measure LH and FSH
• Elevated LH and FSH suggest primary hypogonadism; low or lower-than-normal LH and FSH levels suggest secondary hypogonadism
• Normal LH and FSH with low testosterone suggest a primary defect in the hypothalamus and/or the pituitary.
• Unless fertility is an issue, estimation of LH alone is sufficient
• If the total testosterone concentration is less than 150 ng/dl, pituitary imaging, and prolactin levels are recommended to evaluate for structural lesions in the hypothalamus-pituitary region

Causes of Androgen Deficiency in the Adult Male

• Causes are multifactorial, including factors related to the cerebral cortex, hypothalamus, pituitary, testes and target organs

Cerebral Cortex

• Stress: Testosterone levels rise when a male achieves or defends a dominant position Testosterone levels fall when a male is dominated Excessive physical/mental stress activates the HPA axis and decreases androgens
• Physical Illness
• Drugs: Psychotropics, Antidepressants, anxiolytics, antiepileptics, antipsychotics

Hypothalamus and Pituitary

• Age
• GnRH decreased, which is related to opiate use (heroin, morphine, methadone)
• High prolactin levels increase with stress and prolactinomas
• Chronic renal failure
• Hypothyroidism
• Drugs can raise prolactin levels

Medications That Can Raise Prolactin Levels

• Drugs that are dopamine antagonists: Phenothiazines and imipramine
• Drugs that interfere with dopamine synthesis: Alpha-methyldopa
• Drugs that deplete dopamine stores: Reserpine
• Drugs that directly stimulate prolactin production, H2-blockers, Estrogens,

Testes

• Impaired development: Non-descent or late descent
• Heredity and familial influences: Diet, Physical activity
• Infections: Mumps, Epstein-Barr, Herpes, Coxsackie, Arbodengue (Dengue fever), Marburg virus, Gonorrhea, Chlamydia, COVID-19
• Age
• Alcohol: Short-term low dose ETOH increases testosterone; Short-term low dose or high dose ETOH decreases testosterone Physical stress immediately before ETOH use prolongs the reduction in testosterone Alcoholics may have thyroid and adrenal dysfunction which lowers the testosterone and they may have high estrogen levels
• Diet: Low cholesterol diets may lower testosterone Vegetarian diets, particularly if low in protein, can increase SHBG which lowers free testosterone Also, men on low-fat, high-fiber, vegetarian diets have lower total and free testosterone which was reversed when they went back on their regular diet High protein, low carb eating programs may increase testosterone
• Diabetes
• Temperature: Varicocele and hydrocele impair the temperature regulation of the scrotum which keeps the testes at the right temperature Scrotal cooling may be improved by wearing boxer shorts, avoiding tight jeans and long periods of driving
• Trauma: Injury, Surgery
• Drugs: Psychotropic drugs, Aminoglutethimide, Ketoconazole, Cimetidine, Spironolactone, Cyproterone acetate, Barbiturates, Anticonvulsants, Digoxin, HMG-CoA reductase inhibitors, Chemotherapy, Cannabinoids, Heroin/methadone Identification of the drug of abuse is important because the discontinuation of the substance can reverse the clinical syndrome

Target organs

• Age
• Receptor anomalies
• Reduction and down-regulation
• Connective-tissue thickening
• Drugs like Aromatase inhibitors & Alphal and alpha2 adrenoreceptor blocking agents can increase tissue resistance to androgen action

Functions of Testosterone

• Sex hormone and receptors all over a male's body
• Involved in the making of protein and muscle formation
• Helps manufacture bone and improves oxygen uptake throughout the body
• Aids in controlling blood sugar and is needed for normal sperm development
• Aids in aids in mental concentration and Improves mood
• Regulates acute HPA responses under dominance challenge
• Regulates the population of thromboxane A2 receptors on megakaryocytes and platelets (platelet aggregation)
• Helps regulate cholesterol; helps maintain a powerful immune system
• Helps protect the brain against Alzheimer's disease

Testosterone Biosynthesis

• 95% of the circulating testosterone in the blood is made in the Leydig cells of the testes - 6-7 mg a day in the healthy adult male
• The remaining 5% is made in the adrenal glands
• The making of testosterone is regulated by biofeedback mechanism & influenced by physiological, pharmacological, and lifestyle factors

Feedback Mechanism

• Production of testosterone in testis is controlled by the pituitary gland

Gonadotropin-Releasing Hormone (GnRH)

• GnRH is released into the pituitary portal circulation from the hypothalamus
• It synapses with cells that produce melanocortin-related peptides, metabolism of NE and GABA which all affect GnRH secretion
• GnRH is the only releasing factor for LH and FSH.
• The frequency of the GnRH pulses depends on stimulation from surrounding cells and noradrenergic activity; Inhibition from circulating androgens/estrogens; - Dopaminergic/Serotonergic/GABAergic neurons and opioid peptides reduce the negative feedback of gonadal steroids
• Both testosterone and dihydrotestosterone (DHT) act mostly on the hypothalamic level by reducing the GnRH pulse frequency
• Estrogens decrease the gonadotropin secretion by decreasing the amplitude of LH and FSH peaks at the pituitary

Gonadotropins

• Both LH and FSH are made in the same anterior cells of the pituitary; However, they are stored in different secretion granules
• The pattern of release is different between LH and FSH
• There is more constant secretion of FSH and is preferentially released with lower frequencies of GnRH pulses

Testicular Synthesis

• Biosynthesis of testosterone in leydig cells is controlled by the availability of cholesterol in outer membrane of mitochondria, the rate of transfer to membrane with StAR protein or cytochrome P450

Metabolism of Androgens

• Testosterone has a half-life in blood stream of 12 minutes
• The liver breaks down Testosterone into metabolites that are then excreted via the urine and skin
• Active metabolites include DHT, estrone, estradiol
• Conversion of Testosterone into DHT occurs under the actin of three types of 5 alpha-reductase

Transport of Androgens

• Testosterone cannot be stored in the testis
• Testosterone is found as 2% in the bioavailable form in the plasma; 54% is weakly bound to albumin; 44% is bound to sex hormone binding globulin (SHBG); The affinity of SHBG for DHT is 1.3x higher for testosterone and 4x higher than for estradiol

Sex Hormone Binding Globulin

• SHBG is a protein that transports androgens and estradiol in men in the blood & regulates bioavailability and access to target cells
• SHBG binds more to androgens than estrogens and also mediates signaling
• SHBG may increase with age so as hormone levels decline even lower levels may be available since bound to SHBG
• Most of the testosterone in the body is bound to albumin or SHBG
• The combination of free and albumin-bound testosterone determines the bio-available amount
• High estrogen levels increase the body's production of SHBG; high testosterone levels depress production of SHBG

Signs and Symptoms of Andropause:

• Fatigue, tiredness, loss of energy, depression, low or negative mood, and irritability. The Loss of memory or concentration are also markers.
• Patients may experience anxiety or nervousness, weight gain, Loss of sex drive or libido, Loss of erections or problems during sex, backache, joint pains, or stiffness, Loss of fitness,.
• It might cause feeling over-stressed, decline in job performance, decline in physical abilities.
• Symptoms also include Bone loss, Elevated cholesterol Increased risk of heart disease, increased risk of insulin resistance, diabetes and metabolic syndrome,,decreased intensity of orgasms

Testosterone & Coronary Heart Disease (CHD)

• Low Total Testosterone, Free Testosterone & Bioavailable Testosterone are related to increased risk of coronary heart disease, mortality, erectile dysfunction and heart conditions
• Low testosterone levels cause men to begin to heart failure after age 40
• Severity of coronary disorders is adverse in men with subtotal testosterone
• Higher incidence of coronary atherosclerosis, coronary calcium score, peripheral artery disorders & aortic calcification
• Low serum levels are inverted to carotid intima-media thickness and plaque score

Testosterone Levels Impact on Memory:

• Higher ratio of total to SHBG relates to slow rates of Alzheimer’s
• Testosterone plays a major role in brain functioning and is important for decreasing memory loss
• Subclinical androgen deficiency increases amyloid-b related peptides
• Increased or Decreased levels effect the spinal and mathematical reasoning

Low Testosterone and Bone Health

• Decreases can cause low bone mineral density which is likely to increase, a possible link with joint problems
• Some cases may include Osteoporosis which can cause severe trauma
• Decreases and can increase likely increase the risk for hip fracture

Low Testosterone and Inflammation

• The levels of free-testosterone are negatively related to blood serum
• Chronic Inflammation has excessive visceral fat which causes major inflammatory effects

Replacement and Balance of Male Hormones

• Estrone/Estradiol, Progesterone, and dihydrotestosterone all determine proper function
• Testosterone also balances

Levels to examine in Lab Work

• Total testosterone, free testosterone
• DHT
• Estradiol
• Estrone
• DHEA
• CBC
• Cortisol
• SHBG
• Progesterone
• PSA
• Albumin
• FSH, LH
• SMA

PSA Evaluation

• 4.0 but rising by 1.5 ng/ml in one year or 0.75 ng/ml per year over two years requires evaluation
• PSA of more then 4 requires a further look into the patients background
• Digital rectal examination every six months with testosterone therapy

Estrogen

• In males, They make estrone, estradiol, and estriol.
• Measure both estrone and estradiol
• Neede in small amounts to maintain bone structure or memory
• Are essential for modulating libido or function in spermatogenesis

Progesterone

• A hormone is produced in males, and it has many great functions in the body.
• Blocks or stimulates various part of the body

Potential benefits of Progesterone

• Modulates apoptosis
• inflammation, oxidative stress, or excitotoxicity
• Limits cellular necrosis
• Protects and rebuilds a blood-brain barrier

Side Effects of Progesterone

• Commonly prescribed on the skin + mixed testosterone through syringe or pump
• Used IV for TBI and CVA

Dihydrotestosterone

• Most potent and naturally occurring
• Synthesized from conversion
• Responsible for male sex-specific with prostate

Levels of DHT to be aware of

• Overdose; Hirsutism, BPH, Male pattern baldness.
• A five alpha reductase with the effect

5ARIS

• a growth promoting effect on greater prostate cells
• high levels of androgen can activate stimulate the androgen with receptors to release PSA
• DHT interacts with elevated prostate
• A reduction inhibits the prostate growth which increases the levels to a normal amount

DHEA Hormones

• Increases strength/ mass and decreased the amount of triglycerides
• A damagin eEffect to increase
• Positive relationship in memory

DHEA and bone

• Studies found an increase in serum which could reduce possible
• These hormones create bone mass which are found to be high in elderly men

Benefits of a DHEA

• May reduce to cognitive problems while having neuroprotective power

Benefits to High Hdl-c

• Can help lower cholesterol
• Used to help for a good cardio plan

TRT information on different applications

• creams help for a good safety profiel and they're good in the tissue
• the gel is helpful to dry but not if there a swimming activity before getting it dry
• for transdermal patches they can help to rotate the same site that's been used
• also they can cause irritation in skin

Benefits to TRT with Transbuccal tablet

• The testosterone can absorb after the food intakes
• the taste can be bitter and have anxiety

Steriolized compound injections

• dose is usually 0.5 mg to 1 Mg'ml with certain testosterone

TRT INJECTIONS

• not to take a testosterone SQ with the package insert because the patient may be affected

Benefits with Testosterone + Estradiol in bone health

• reduce risk of fracture for better bones
• if estrogen levels can elevate then a high range of benefits can occur