Introduction

When the body is functioning properly, it is due to the hormones working on each organ and body system for individuals to achieve overall health and wellness. In males, the lead hormone is testosterone, and when hormones get off-balance it can cause problems to the male body. Hormones naturally decline due to age and chronic illnesses can also affect hormones causing individuals to be in pain and disrupting everyday activities. Part one explains what happens when there is low testosterone in a male body and part two explains what are the causes for low testosterone. Over the last decade, many of our patients asked complex and insightful questions about hormone replacement therapies. By referring patients to qualified and skilled providers who specialized in hormone wellness services, we advise our patients, appropriately, to refer to our associated medical providers based on their examination. We find that education is the key to asking valuable questions to our providers. Dr. Jimenez DC provides this information as an educational service only. Disclaimer

What Is Hormone Replacement Therapy?

In older males, hormones naturally decline due to age and the testosterone levels start to get off-balance when there is an overproduction from the adrenal glands. With hormone replacement therapy or HRT, it can help regulate and replenish testosterone levels in the body. Not only that but HRT can even help prolong the progress of prostate cancer and lower the overproduction of androgen hormones from the adrenal glands.

New Guidelines Presented at the American Academy of Anti-Aging.

Testosterone Replacement Therapy & Erectile Dysfunction

Erectile dysfunction is a common complaint that older males go through when they age. Testosterone replacement therapy or TRT shows promising potential by replenishing low testosterone levels and improving erectile dysfunction.

• Review of studies done on TRT and ED. (Rizk et al, 2017)
• The recently published Testosterone Trials – a set of RCTs of 790 men with late
  onset hypogonadism randomly assigned to either testosterone gel or a placebo –
  demonstrated that after 1 year of treatment that men who used testosterone gel
  had an IIEF-ED score 2.64 points [95% Confidence Interval (CI): 1.06 – 4.02]
  greater than men who had been assigned to the placebo arm
• “The available literature supports a role for TRT in men with low testosterone
  levels, ED, and low libido, with symptomatic improvement in these men.”

TRT and Cognitive Function

Since testosterone correlated with cognitive function, TRT improves it. High free testosterone, was associated with better performance on tests from memory, executive function, and spatial ability. Not only that, TRT can reduce the risk for Alzheimer’s and improve cerebral blood flow.

• Androgen supplementation in elderly
  hypogonadal men improve spatial cognition
  and verbal fluency
• In elderly men without dementia, it may reduce
  working memory errors
•  Testosterone or DHT therapy in men aged 34 to
  70 years improved verbal memory and spatial
  memory respectively

Testosterone and Alzheimer’s

Alzheimer’s disease is a progressive neurological disorder that causes the brain to shrink and is one of the most common causes of dementia. Alzheimer’s can cause a person to decline their thinking, behavioral and social skills while also affecting their ability to function independently.

• TRT prevents the production of beta-amyloid precursor
  protein in men
  – Gouras GK et al. Testosterone reduces neuronal secretion of
  Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci USA 2000 Feb
  1;97(3):1202-5
• Alzheimer’s male patients TRT treated improved over 1 year;
  control group deteriorated
  – Tan RS A pilot study on the effects of testosterone in the hypogonadal aging male
  patients with Alzheimer’s disease. Aging Male. 2003 Mar;6(1):13-7

Testosterone Replacement Therapy can have a beneficial impact on males which includes:

• Erectile Dysfunction
• Cognitive function in Alzheimer’s
• Bone Mass Density
• Body composition
• Metabolic parameters
• Maybe blood pressure

Testosterone and Inflammation

Testosterone therapy created a more anti-inflammatory profile by lowering fewer inflammatory cytokines like TNF and IL-1 beta. TRT can cause the body to produce more anti-inflammatory cytokines like IL-10 and even help lower total cholesterol.

• Inflammation plays a central pathogenic role in the
  initiation and progression of coronary atheroma
  and its clinical consequences.
• Cytokines are the mediators of cellular
  inflammation and promote local inflammation of
  the arterial wall, which may lead to vascular
  smooth muscle apoptosis, degradation of the fibrin
  cap and plaque rupture

The Baseline Testing for Testosterone Deficiency

The guidelines recommend collecting an early-morning sample to compensate for the natural diurnal variation in testosterone levels. But for men 45 and older, this is unnecessary. About 2569 men at Minneapolis VA looked at testosterone levels based on age throughout the day. Only the youngest men (<45) had significant differences based on age and the different tests to detect testosterone deficiency include:

• Blood testing (serum)
  – Total/free testosterone
  – SHBG
  – DHT
  – DHEA
  – Estradiol
  – LH/FSH
• 24-hour urine testing
• Saliva testing
• Blood spot testing
• Dried urine test

Methods of Testosterone Therapy

There are many methods of testosterone therapy for males that have low levels of testosterone. This includes:

• Transdermal patch
• Topical Testosterone
• Injectable Testosterone
• Oral
• Pellets
• Clomiphene
• HGH

TRT: Transdermal Patches

Transdermal Testosterone Patches are available in 2-mg and 4 mg preparations and the typical starting dose is 4-mg/day; can increase to 8-mg or decrease to 2 -mg as needed. What you need to do is:

• Applied at night to a clean, dry area of skin on the back, stomach, upper arms, or thighs.
• Sites should be rotated daily, allowing 7 days before re-applying to the same site
• Side effects:
  – Skin irritation, vesicle formation, contact dermatitis,
  headache, and depression

TRT: Gel Formulations

Testosterone Gels are topical testosterone and can be applied in the morning to the shoulders, abdomen, or upper arm; preferably at the same location every day. What you need to do:

• Use gloves or wash hands after application- They will have hormone on hands for 4-12 hours
• Allow gel to dry (10-15 min) before covering with clothing
• Wait 4 hours prior to showering or swimming
• Wash with soap and water if skin-to-skin contact with another person
  anticipated
  – Dosing: 1% or 1.62% generally available
  – 5 grams (50 mg testosterone) daily, can be increased to 7.5 – 10 grams as needed or 40.5 mg of the 1.62%, can be increased in increments of 20.25mg
• Side effects: acne, headaches, emotional lability, nervousness, gynecomastia, mastodynia, insomnia, hypertension, hot flashes, polycythemia, and increased PSA
  – Local skin irritation occurs much less frequently than with patches
  – Major issue is transference
  – Substantial variation in absorption

Injectable Testosterone

Injectable testosterone esters in oil are slowly absorbed from the lipid
phase. There are different esters absorb at various rates giving them different
half-lives:

• T cypionate 12 days
• T enanthate 10.5 days
• T propionate 4.5 days

The longer-acting esters may convert more readily to estrogen and peak levels after IM use are greater than topical use but so is peak-trough fluctuation. There are two types of testosterone injections, there are testosterone enanthate or cypionate injections. What these two injections do are:

• Commercially available or compounded
• Q2 weeks 200mg IM (Older method)
  – Supraphysiologic levels followed by low levels
  – More aromatization to estradiol
  – Less DHT than transdermal
• Weekly dose 100mg IM
  – Better physiologic, stable levels
  – Less aromatization to estradiol
• Bi-weekly dose 25-50mg IM or SQ (more irritating)
  – SQ may have more consistent levels (Shippen)
  – SQ is generally preferred by patients and achieves similar levels as IM

Testosterone Undecanoate Oral

The adverse effects are approved 3/2019 and have a BID formulation taken with food. The dosage is about 237 mg bid up to 396 mg bid (avail as 158, 198, and 237 mg soft gels). By taking testosterone undecanoate orally it is best to know that it can increase BP (Black box warning of the risk of major cardiac events), it can bypass the liver because it is absorbed through lymphatic circulation and it can avoid skin irritation (patches), transference (Topicals), pain (injections).

Testosterone Pellets

Testosterone Pellets can offer the longest duration of action with prolonged zero-order, steady-state characteristics. They can last 3 to 6 months depending on activity and stress level and are about 75mg per pellet and are measure 3.2 mm (1/8 inch) in diameter and approximately 9 mm in length.

Usages on testosterone pellets:

• 150mg to 450mg SQ Q 3-6 months
• Insert 2 pellets for every 25 mg of testosterone propionate injection needed
  weekly
• Potential drawbacks:
  – Minor office procedure
  – Risk of infection and pellet extrusion
  – Inability to remove pellet if a contraindication to testosterone therapy develops

Clomiphene

Clomiphene citrate is used off-label to attempt to increase sperm density in men with oligospermia or azoospermia and normal to low serum testosterone concentrations. Clomiphene is also used for testosterone deficiency in men who wish to preserve or improve fertility. Clomiphene is a weak estrogen receptor antagonist that stimulates increased pulsatile GnRH secretion from the hypothalamus and subsequent pituitary gonadotropin (FSH, LH) release. There have been multiple studies that suggest clomiphene citrate can improve semen parameters in patients with oligo-, oligo astheno-, and azoospermia. Clomiphene dosing includes:

• 25 – 50 mg every other day or 12.5 mg QD
• Clomiphene given by 2 different dosing regimens were compared in 89 oligospermic men. The group receiving clomiphene 25 mg every other day showed a greater overall sperm improvement response (80%) than the group receiving clomiphene 25 mg daily for 25 days (50%). Increases in sperm concentration and total sperm count were significantly greater with the lower dose regimen. Pregnancy rates in the study were not significantly different during the 6 month
  follow-up period (Homonnai et al, 1988).
• May raise Testosterone levels w/ less impact on libido than Testosterone

Clomiphene side effects include:

• Flushing, vasomotor, abdominal bloating, discomfort,
  distension, nausea, vomiting, headache, visual disturbance, breast pain
  Serious side effects: acute pancreatitis, functional visual loss, psychotic
  disorder, a disorder of menstruation, hyperstimulation of ovaries,
  hypertrophy of ovary, ovarian cancer
• Watch out for pituitary apoplexy
• Contraindications: liver disease or dysfunction, endometrial carcinoma,
  ovarian cysts (not polycystic ovarian syndrome), undiagnosed uterine
  bleeding, pregnancy

HCG

HCG does not negatively impact fertility/sperm count as testosterone often does and does not cause testicular atrophy. Surprisingly it is identical to LH with some FSH activity stimulating testosterone production by the testicle. HCG Dosing includes:

• 1000-3000 units intramuscularly 2-3 times weekly SC
• Some use along with Testosterone for testicular preservation at doses from 500-1500 IU / week. No clear references for this.
• Antibody production against the hCG is possible
  – Most protocols recommend 2 months on and one month off hCG

HCG side effects and precautions include:

• Anaphylaxis
• Do not use in cancer or tumors
• May cause water retention
• VTE has been reported
• Intracranial lesions
• Prostate cancer or other androgen-dependent neoplasms
• Do not use orally, contains benzyl alcohol
• Administration of chorionic gonadotropin can stimulate the production of antibodies.
• In rare cases, these antibodies may result in resistance to treatment by binding chorionic gonadotropin

Conclusion

All in all, hormones play a functional role in the body. When there are unwanted pathogens that entered the body and cause harm it can lead the body to be off-balance. In this case with hormones, when the unwanted pathogens cause the body to overproduce hormones, it can cause chronic illnesses that can cause pain and affect a person’s overall health and wellness.

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