5 Questions and Answers on Male Hypogonadism and Testosterone Deficiency

Male Hypogonadism (testosterone deficiency) is a hormone disorder in which the body does not produce enough testosterone. This condition affects 10% of all adult men and the majority of men over age 80 years.

This post will review the symptoms, causes, and treatments of male hypogonadism, and will answer some typical questions from patients with this condition.

Overview: symptoms, causes, and treatments

Possible symptoms

  • Decreased sexual desire
  • Erectile dysfunction
  • Diminished physical strength and endurance
  • Depression or irritability

Possible causes:

  • Normal aging, obesity, physical illness, narcotic analgesics
  • Pituitary hormone deficiency
  • Testicular failure

Treatments may include:

  • Testosterone skin gels
  • Testosterone injections
  • Testosterone skin patches
  • Clomiphine citrate oral tablets
  • Gonadotropin injections (hCG, Follistim)

Questions patients ask about testosterone deficiency:

Question:  I’ve been applying a testosterone gel to my shoulders every morning. My wife is now afraid to sleep with me, because she’s worried that some gel will transfer onto her and make her grow a beard. What are my options?

Your wife has some justifiable concern, but it is very rare for a wife or partner to receive significant testosterone transfer. However, it’s still wise to take precautions.  Transdermal testosterone gel (Androgel, Fortesta, and Testim) are all testosterone gels that men generally apply  in the morning and let air dry for 5-10 minutes before dressing. The testosterone absorbs into the skin and is slowly released, giving stable serum testosterone levels over the course of the day.  Little gel remains on the skin by the evening to transfer to your wife or partner; but deliberate, prolonged skin-to-skin contact could transfer a small but significant amount of testosterone.  So I advise simply shower in the evening and/or wear a T-shirt to bed.

If your wife remains concerned, you may consider other options for testosterone replacement:

  • Axiron is a testosterone gel that is applied daily to each axilla (arm pit), which puts it in a more enclosed area where transfer is less likely.
  • Testosterone patches include Androderm patches that adhere tightly to the skin, but may cause skin irritation that can be severe. Few of my patients like the patch system, but patches remain an option because the testosterone is covered and cannot transfer to your partner.
  • Testosterone injections are an old standby to consider. Testosterone cypionate and testosterone enanthate are formulations of testosterone in oil that are injected into the gluteus (butt) every 1 to 3 weeks. With injections, there would be no transfer to your wife. But with injections, testosterone levels vary more than with other testosterone replacement options. Also, it is given with a large needle and can be difficult for some men to self-inject. However, injectable testosterone is relatively inexpensive and most partners don’t seem to mind giving their man the shots.
  • Testosterone buccal (Striant) tablets are placed between the upper lip and gum. One or two 30-mg tablets can be used and changed every 12 hours. They should not be chewed or swallowed. Some men get used to this, but their testosterone levels usually remain in the low range of normal.
  • Oral testosterone undecanoate (Tlandro, Jatenzo, Aveed) are oral testosterone preparations that are available as capsules.  It must be taken orally twice daily with food.

If your low serum testosterone is due to a pituitary or hypothalamic issue (normal or low serum LH), then hCG injections or oral clomiphene are options:

  • Human chorionic gonadotropin (hCG) is an injectable preparation that is equivalent to luteinizing hormone (LH) that stimulates the Leydig cells of the testicles to produce testosterone.  It must be given by injection 3 times weekly.  Many men can attain testosterone levels that are more reliably with the mid to upper range of normal with hCG.
  • Clomiphene is an oral medication that can be quite effective for some men with partial testosterone deficiency or low sperm counts. it’s a pill and costs much less than testosterone gels. Although known for stimulating ovulation in women, men may use it for partial testosterone deficiency. Clomiphene tablets are taken orally at a starting dose of 25 mg every 2 days, titrated upwards to a maximum dose of 50 mg daily in order to achieve a target serum testosterone of about 550 ng/mL.  A disadvantage to clomiphene is that it increases the risk for blood clotting, as with oral estrogen.

Question:  I’ve had surgery for a craniopharyngioma (a type of brain tumor), and as result I now have hypopituitarism. I’m using Androgel and my testosterone levels are normal, but my sperm count is zero and I want to be able to have children. What can I do?

The tumor (or surgery to remove it) damaged your pituitary or hypothalamus, knocking out the cells that produce luteinizing hormone (LH) and follicular stimulating hormone (FSH). LH stimulates the testicles to secrete testosterone, while FSH stimulates the testicles to produce sperm. Both are required for sperm to develop. If you had already experienced a normal puberty and testicular development, your sperm count can probably be improved with treatment.

Androgel increases your serum testosterone, but the testosterone level in your testicles must be much higher to resume testosterone production and allow spermatogenesis.  So transdermal testosteron treatment can be changed to human chorionic gonadotropin (hCG) that is similar to LH, a hormone your body should be producing.  You would need to inject hCG into your thigh three times weekly, with the dose of hCG being adjusted to maintain your serum testosterone in the upper range of normal. After several months, you’ll undergo another semen analysis; if the sperm count remains below 15 million/mL, FSH (brand name: Follistim) injections can be added 3 times weekly. Unfortunately, Follistim is EXTREMELY expensive and may not be covered by insurance. Therefore, it may make sense to work with a sperm specialist urologist who will do serial sperm counts and collect and cryopreserve (deep freeze) the sperm. This would allow you to take the Follistim for the shortest period of time and minimize your expense.

Once your body is producing sperm again, I recommend timing your intercourse with your partner’s ovulation. At other times of the month, your urologist’s laboratory can collect sperm to cryopreserve for later use in the event that your partner hasn’t become pregnant.  If further assistance is needed, you would continue the hCG injections, and your partner’s OB/ Gyn would perform intravaginal insemination to increase the odds of fertilization. If all else fails, in-vitro fertilization is an option.  Some of my patients have experienced an improved sense of well being while taking hCG injections, compared to standard testosterone replacement therapy, so some men continue hCG injections.

Hypopituitarism can also be congenital (e.g. Kallman syndrome or PROP1 gene mutations), or it may develop in childhood, due to tumors or other problems.  In such cases, boys do not enter puberty. With childhood hypopituitarism, if puberty hasn’t begun by age 14, we can give hCG injections to induce puberty and testicular enlargement. Later, the hCG can be changed to testosterone replacement.  When fertility is desired, hCG and Follistim can be given as described above.  A common problem with childhood hypopituitarism is that many men delay having children until their 30s, when their testicles may not respond sufficiently to hCG/FSH to allow natural fertility.  However, in-vitro fertilization of the ovum (intracytoplasmic sperm injection, ICSI) is still usually possible.

Question: What are the possible benefits and risks of testosterone therapy?

Possible benefits of testosterone replacement therapy:

  • Improved sex drive and erections.
  • Protection against osteoporosis.
  • Improved overall mood, energy level, and sense of vitality.
  • Increased body sex hair.
  • Better exercise endurance and muscle strength.

However, testosterone will not solve all your problems. Sexual desire depends upon many other things, including your situation, partner, and frame of mind. The strength of erections usually wanes with age and can be reduced by a wide variety of medications. Erectile dysfunction (ED) is very common in men with no testosterone deficiency whatsoever.

Risks of testosterone replacement therapy:

  • Increased risk of acute coronary syndrome (heart attack) in men older than age 65 with cardiac risk factors or preexisting angina, possibly due to the decrease in serum HDL (“good”) cholesterol that occurs with testosterone therapy. However, a study from the University of British Columbia reported no adverse cardiovascular effects from testosterone therapy in men with heart failure.
  • Aggravation of benign prostatic hypertrophy (BPH), although it does not commonly worsen voiding problems in younger men.  In younger men, testosterone replacement therapy does not appear to increase the incidence of prostate cancer.  However, in elderly men, testosterone appears to increase the risk of prostate-related symptoms and may possibly increase the risk of clinically significant prostate cancer, compared to elderly peers with low testosterone.  Needless to say, testosterone is contraindicated in the presence of active prostate cancer. Therefore, it is reasonable to obtain a serum PSA before beginning testosterone. Men with an elevated or high-normal PSA or who have had a prior prostatectomy for low-grade prostate cancer, should not receive testosterone replacement therapy unless they are followed carefully for increasing PSA levels that can signal the the emergence of prostate cancer or prostate-related symptoms.
  • Development of an excessively high red blood count (erythrocytosis, polycythemia), which is more common with intramuscular injections of testosterone, compared to other treatments.
  • Aggravation of sleep apnea. Some surveillance for sleep apnea is prudent during testosterone therapy.
  • Development of acne (usually mild).
  • Enlargement of the breasts (gynecomastia). Such enlargement is usually mild and may regress spontaneously; switching from testosterone injections to other treatments may help this condition.  Male breast cancer can be stimulated by testosterone therapy.
  • Interactions with certain drugs: coumadin, cyclosporine, tacrolimus, and tolvaptan; potentiation of insulin and other drugs for diabetes.

Question: I have testicular failure with a very low testosterone and a high serum luteinizing hormone (LH) level.  What could have caused this?  Also, my breasts are large and I’m worried that I may have Klinefelter syndrome!

Testicular failure can be caused by viral infection (e.g., mumps), irradiation, cancer chemotherapy, radioisotope therapy, autoimmunity, kidney failure, and male menopause.  In men who have had one testicle removed for cancer, the remaining testicle can fail spontaneously.  Rare causes of testosterone deficiency include genetic deficiencies in certain enzymes that are important for the synthesis of testosterone.  When the testicles fail, the pituitary tries to stimulate them by secreting more luteinizing hormone (LH), such that serum LH levels are usually elevated.

Klinefelter syndrome (47,XXY and its variants) is the most common chromosomal abnormality in men, with an incidence of about 1:500.  It is caused by the expression of an abnormal genetic karyotype with an extra X chromosome, classically 47,XXY.  Other forms (46,XY/47,XXY mosaicism, 48,XXYY, 48,XXXY, or 46,XX males) are also common.  The diagnosis of Klinefelter syndrome is confirmed by either of two blood tests: 1) genetic karyotyping; 2) testing for RNA X-inactive-specific transcriptase (XIST) in peripheral blood leukocytes by polymerase chain reaction (PCR).

About 85% of men with Klinefelter syndrome develop some breast enlargement (gynecomastia) at puberty.  Mental acuity is usually normal, but some men have problems with cognition, coordination, or social skills.  Other symptoms may include inward-curved pinky finger (clinodactyly) or abnormal bone fusions (synostosis).  There is an increased lifetime risk for breast cancer, chronic lung disease, varicosities of the legs, and diabetes mellitus.

For men with Klinefelter syndrome, some sperm production is often present during their early teens, such that sperm banking can be considered.  But by adulthood, most men (about 95%) with classic Klinefelter syndrome have undetectable sperm (azoospermia).  However, men with 46,XY/47,XXY mosaicism may have spontaneous fertility.  Also, testicular biopsy reveals some sperm in up to 50% of men with the disease, allowing some of these men to achieve fertility with the use of in-vitro fertilization using intracytoplasmic sperm injection (ICSI).

Question: I’m 75 years old and my serum testosterone levels are slightly low and my serum LH is normal.  What does this mean?  Would taking testosterone help me?

The evaluation for testosterone deficiency must begin with a proper morning blood test for serum testosterone and free testosterone.  A low level should be verified with a repeat assay, and further evaluated with serum luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels.  Serum testosterone is considered low when it is confirmed to be below 320 ng/dL (11 nmol/L).  Serum free testosterone is considered low when it is confirmed to be below 64 pg/mL (220 pmol/L).

The main causes of mild testosterone deficiency (serum testosterone 150 – 300 ng/dL with a normal LH) include functional conditions such as obesity, acute illness, or normal aging.  Serum testosterone levels in men are highest at age 20 – 30 years and slightly lower at age 30 – 40 years; testosterone levels tend to decline gradually after age 40 years.  After age 40, serum total testosterone declines variably by an average of 1 – 2% per year; serum free testosterone levels decline even faster, since sex hormone binding globulin increases with age.  After age 70 years, 28% of men have low serum total testosterone and 68% have low serum free testosterone levels, compared with the levels found in young men.  Usually, the serum LH is normal, indicating no testicular damage.  After age 70, LH levels tend to rise, indicating a contribution of primary testicular (gonadal) dysfunction with advanced age.  Testosterone deficiency with normal aging is known as androgen deficiency in aging men (ADAM).

If the serum testosterone is persistently low, with a low/normal serum LH and normal or high PRL, it is possible to have a pituitary-region tumor, some of which secrete PRL. However, many other factors can elevate serum PRL.  Another test that may be obtained is a serum estradiol (estrogen) level, which may be elevated in conditions such as cirrhosis or in rare cases of estrogen-secreting tumors (testicular Leydig cell tumor or adrenal carcinoma).  If you have no discernible definite cause for hypogonadotropic hypogonadism, you may be screened for hemochromatosis with a blood test for serum iron concentration and transferrin saturation.  An MRI of the pituitary and hypothalamic region may be obtained to detect a tumor or other lesion.  MRI pituitary scanning is particularly important for men with headaches, visual field abnormalities, a high serum PRL, very low serum testosterone, low or normal serum LH, or if other pituitary hormone deficiencies are present.  In many cases, the cause of hypogonadotropic hypogonadism remains unknown (idiopathic).

Opting for testosterone replacement therapy: For men with partial testosterone deficiency with a low/normal serum LH, the decision about whether to begin treatment is difficult.  A multicenter European study concluded that men will likely benefit from treatment if their serum total or free testosterone is persistently low and they have at least three of the following six symptoms: erectile dysfunction, poor morning erection, low libido, depression, fatigue, or inability to perform vigorous activity.  In cases of borderline low serum testosterone levels and marginal hypogonadal symptoms, the potential benefits versus risks (see above) of testosterone replacement therapy must be considered. Sometimes, it is reasonable to have a trial of testosterone or clomiphene for several months, while monitoring the response.

Further reading on male hypogonadism

You can find free abstracts for all the following articles by going to PubMed and plugging in the PMID number that I’ve listed at the end of each reference.

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