- Your Teenage Son May Have Hypogonadism
- Clinical Significance
- Testosterone Therapy in Boys with Delayed Puberty
- Low Testosterone (Male Hypogonadism): Management and Treatment
- Low Testosterone
- Topic Overview
Your Teenage Son May Have Hypogonadism
Boys often hit a growth spurt at about 14 — that’s when they start to develop the muscles, physical features, deepening voice, and body hair of an adult. Low testosterone, medically known as hypogonadism in boys, may keep a young teen from developing these characteristics at the same time and pace as his peers. Hormone replacement therapy, which is essentially a small dose of testosterone, might be necessary to spur development.
“Often, the boy is the first person to notice it because, when he’s in the locker room, he starts to see that other boys are developing secondary sexual characteristics in puberty, and he isn’t,” says men’s health expert and endocrinologist Bradley Anawalt, MD, a professor of medicine at the University of Washington in Seattle. “And he’s probably more likely to talk to his father about this than his mother.”
Dr. Anawalt says that parents might not have any reason to suspect hypogonadism unless they notice that their son’s pals are sprouting up and their son isn’t. For many young men, he points out, this is simply a delay in development that will ultimately correct itself. A look at family history might even reveal that the boy’s father or other male relatives also developed slightly later than their peers. Recent genetic research strongly underscores that the timing of puberty has a genetic basis, and alterations to genes can derail the typical timing of the process. Many young men might find that simply waiting it out is the solution. However, any delayed development can be socially and emotionally difficult for a young man if it doesn’t resolve itself quickly!
Hypogonadism 101: Testosterone is one of the hormones that help guide a boy’s development into a man. The gonads — glands in the testes — produce this hormone. A simple delay in a teen’s development could just mean he has low T compared to his peers at that moment. This delay, called a “constitutional delay of puberty,” can last until age 18 or 19; at that point, a continued delay could trigger greater concern.
However, hypogonadism also can be the result of chromosomal conditions such as Klinefelter syndrome, in which testosterone production might decrease over time, or certain types of medical treatments, infections, and injuries.
Signs of Hypogonadism: With teen boys, hypogonadism is signaled more by what isn’t happening than by what is. For example, says Anawalt, enlarged testicles are the kick-off signal that puberty and the development of secondary sexual characteristics are on the way, but without enough testosterone, this first event doesn’t happen.
“But a boy isn’t likely to notice that his testicles haven’t enlarged,” he points out, and neither are his parents. More noticeable signs are the lack of:
- Pubic hair development
- Deepening voice
- Development of other body hair, such as facial or underarm hair
- Height or growth, compared with peers
- Muscle development, compared with peers
- Growth of penis
For boys, ages 13 and 14 are a critical period of development into puberty. If a boy hasn’t developed enlarged testicles, some body hair, and the beginnings of adult height and musculature by 14, then his doctor might consider testing for hypogonadism.
Testing for Hypogonadism: The testing involved is fairly simple — blood tests that can check on testosterone levels and possibly a full hormone profile, including hormones related to growth. Other tests might be recommended if a boy’s doctor suspects an underlying condition such as Klinefelter syndrome. This chromosomal abnormality, which affects about 1 in 500 men, might be recognized in early childhood, but Anawalt points out that many only find out about it when they don’t experience puberty at the same rate as their friends. Low testosterone is just one part of the syndrome.
Treating Low T: Your child will have several treatment options if diagnosed with low testosterone.
Wait-and-see approach: About two-thirds of young men who have delayed development because of low testosterone will probably develop normally over time.
Testosterone replacement: Anawalt recommends giving young men only about one-fourth the dose of hormone replacement therapy that might be appropriate for low testosterone in men — just enough to jump-start the development process without endangering the young man’s growth. Too much testosterone can cause the growth plates in bone to fuse, ultimately limiting height. Anawalt prefers monthly injections for 6 to 12 months to using testosterone gel. The problem with the gel, he says, is that you can’t completely prevent it from being transferred to other people with whom the young man comes in contact, including younger siblings and romantic partners.
Low testosterone in teen males isn’t unusual, and there are options for managing it, including waiting to find out whether your boy’s body will catch up on its own.
Our results from the UPOD portion of this study indicate that lower levels of testosterone in adult men who are being assessed for possible hypogonadism are consistently associated with lower levels of estradiol, PSA, SHBG, and LH. In this study, associations between testosterone levels and LDH, BMI, BAP, and age appeared to be dependent on whether the men were older or younger than 56 years of age. The other non-hormonal biomarkers of muscle damage (CK), and metabolism (hemoglobin A1c and uric acid) showed either inconsistent or clinically insignificant associations with testosterone levels.
Notably, we observed a significant association between higher vitamin D levels and higher testosterone concentrations only in men older than 56 years of age. Previous studies have yielded conflicting results regarding associations between testosterone and vitamin D levels . Our results therefore suggest the possibility that the age of subjects may play an important role in accounting for some of the variations in vitamin D levels that have been previously observed.
Creatinine levels demonstrated an interesting reverse association with testosterone levels between the younger and older men of our study. Among men younger than 56 years of age, normal testosterone was associated with higher levels of creatinine. Presumably this reflects the fact that creatinine is a surrogate marker of muscle mass , and testosterone stimulates muscle growth. In the older group of men (>56 years of age), the association seemed to be less pronounced and in the opposite direction (i.e., higher testosterone associated with lower creatinine). Since creatinine is also a marker of renal function, our results suggest the possibility that declining renal function could account for the higher levels of creatinine that were observed in the older men with lower testosterone levels. Thus, associations between creatinine levels and testosterone are likely to reflect a complex balance between muscle mass and renal function that varies with age.
The strong and consistent association between lower levels of LH in men with lower levels of testosterone in this study suggests that secondary hypogonadism was a more common etiology than primary hypogonadism in our study population. This finding is consistent with previous studies that have demonstrated that secondary hypogonadism accounts for ~80% of cases of adult men presenting for evaluation of late onset hypogonadism . Hypogonadism is also frequently associated with obesity and other metabolic disturbances that can lower the level of SHBG . The latter association is consistent with the significantly lower levels of SHBG and higher BMI that we observed in this study among men with lower and lowest levels of testosterone. It should be noted, however, that we observed a significant association between BMI and testosterone only in the men who were older than 56 years of age, and even then, the magnitudes of the differences in median BMI were relatively modest.
The lower estradiol that we observed in men with low testosterone in our study is consistent with a previous report . However, we extend this observation by also reporting a significant association between lower testosterone levels and higher BAP levels, primarily in men younger than 56 years of age. BAP is a marker of bone metabolism, and elevated levels in men have been associated with osteoporosis . Reduced estradiol concentrations have important clinical implications, given the critical role of estradiol on bone density, body composition, and sexual function in men . In future studies, therefore, it will be important to correlate the results of bone densitometry to testosterone, BAP and estradiol levels. Although the available evidence is still inconclusive, we speculate that the concurrent presence of low testosterone, low estradiol, and high BAP could turn out to be a clue to the presence of osteoporosis in men younger than 56 years of age.
Median PSA values in this study were 40% higher for the low testosterone group compared with the lowest testosterone group (Table 1; 0.64 µg/L vs 0.90 µg/L). However, there was less than a 6% difference in PSA between the low testosterone (0.90 µg/L) and normal testosterone groups (0.95 µg/L), thereby suggesting a plateau that is consistent with a saturation effect . These results and others demonstrate that PSA is exquisitely sensitive to androgen status, and low testosterone levels are associated with low PSA concentrations . Maximal PSA concentration appears to be achieved at relatively low serum testosterone concentrations. Rastrelli et al. argued that a low PSA level in men older than 40 years suggested the presence of hypogonadism . The presence of a low PSA level may thus provide additional biochemical evidence for systemic testosterone deficiency, which may be of clinical utility in making the diagnosis in borderline clinical cases.
The observation that LDH was elevated in older men with low testosterone was unexpected, and we are not aware of prior studies reporting this finding. LDH is present in all cells, and increased levels are a non-specific indicator of tissue damage, particularly muscle . Since low testosterone levels are associated with decreased muscle mass, we wonder whether this association reflects increased muscle breakdown in the low testosterone state. Our finding that LDH levels are higher in men with low testosterone therefore suggests that there may be value in measuring LDH in men suspected of having low testosterone.
The results from the exploratory, pre-albumin sub-study are intriguing because they provide preliminary evidence of a statistically significant (p < 0.05) trend towards a catabolic state in men with lower levels of testosterone. Because we included in this study only those men who were otherwise healthy and free of serious disease, we believe that this trend was not likely to be just an artifact due to other known causes of changes in transthyretin, such as severe inflammatory disease and malnutrition . We acknowledge, however, that our sample size was relatively small. Our finding will therefore need to be replicated and extended in larger prospective studies. This is important because pre-albumin might have the potential to become an objective, biochemical marker for the catabolic state produced by low testosterone, thereby justifying consideration of therapy to reverse the catabolic state.
Our study has certain other limitations. Because contemporaneous measurements of testosterone and BMI were not available in some study subjects, and because we had only low numbers for some of the measured biomarkers, it was not statistically feasible to correct or adjust for BMI in the associations between the testosterone groups and the biomarkers. Despite this limitation, our study results confirmed and extended previously reported associations between elevated body mass index and low testosterone in men presenting to a tertiary academic medical center
In the UPOD study, we did not control or adjust for the time of the blood draw for testosterone measurements or the general state of health of the study subjects. The timing of the blood draw is important in younger men, whose testosterone levels have diurnal variation, with levels peaking early in the morning , but younger men were not included in this study. In older men (>45 years of age) such as most of those in our study, however, the diurnal effect on testosterone appears to be much less significant . It should also be noted that the men in the UPOD study were all outpatients who were being tested for hypogonadism. None were critically ill or hospitalized, and there is no a priori reason to suspect any bias in the timing of the blood draws or the general state of health between the groups of our study subjects. Hence, we believe that it is not likely that these factors could have accounted for the associations between biomarkers and testosterone that we observed in this study. Nevertheless, we acknowledge that there is still an open question of whether the associations that we observed have anything to do with low testosterone, or if the low testosterone just reflected general health and had no direct relationship to the markers of interest.
Our results, in toto, provide evidence supporting the concept that the effects of testosterone deficiency in men are far-ranging and involve numerous biological systems, as reflected in the broad, systemic set of biological changes that we observed in hormonal and non-hormonal biomarkers. We believe that alterations in these biomarkers may provide useful information that may enhance the accuracy and reliability of serum testosterone alone for the biochemical diagnosis of testosterone deficiency.
Whereas current clinical guidelines emphasize low values of total testosterone concentrations as a requirement for making the diagnosis of testosterone deficiency, it is acknowledged that there is no absolute testosterone concentration that accurately and reliably separates men who do and who do not have testosterone deficiency We believe the results of the present study support the possibility that a set of biomarkers can be used to assist with the identification of these men, including PSA, LDH, estradiol, creatinine, and possibly BAP. We also believe that this approach merits further exploration.
In conclusion, low testosterone levels are associated with significant changes in a variety of non-cardiovascular biomarkers. This finding may lead to improved laboratory diagnosis of men with low testosterone via objective evidence of physiologic changes produced by testosterone deficiency.
Pathology related to testosterone involves either over-production, under-production, receptor insensitivity, or impaired metabolism of testosterone. The following are a few of the more common and highly tested testosterone pathologies.
Over-production of androgens can occur in the following conditions: polycystic ovarian syndrome (PCOS), adrenal virilization/adrenal tumors, ovarian or testicular tumors, Cushing syndrome, and as a result of exogenous steroid use. To better understand some of these pathologies it is important to note the differences between testosterone and dehydroepiandrosterone (DHEA). DHEA is a relatively weak androgen produced by the adrenals and ovaries/testes. DHEA serves as a precursor for other hormones including testosterone and estrogen. The sulfated form of DHEA, DHEAS, is specific for the adrenal glands. In polycystic ovary syndrome (PCOS), abnormal gonadotropin-releasing hormone (GnRH) secretion leads to an increase in LH secretion. LH stimulates androgen production by ovarian theca cells which leads to hirsutism, male escutcheon, acne and androgenic alopecia in women affected with PCOS. In adrenal and ovarian tumors, there is usually rapidly progressing androgenic symptoms (hirsutism, virilization). If testosterone is elevated and DHEAS is normal, this is most likely from an ovarian tumor. If DHEAS is elevated and testosterone is relatively normal, this is most likely an adrenal tumor.
Decreased production of testosterone can occur with aging, certain medications, chemotherapy, hypothalamus-pituitary axis disorders, primary hypogonadism, cryptorchidism and orchitis, and with genetic disorders such as Klinefelter and Kallmann syndrome. Klinefelter syndrome is the most common congenital abnormality that results in primary hypogonadism. In Klinefelter, there is dysgenesis of seminiferous tubules and loss of Sertoli cells which leads to a decrease in inhibin levels and a resultant increase in FSH. FSH upregulates aromatase leading to increased conversion of androgens to estrogens. In Klinefelter, there is also Leydig cell dysfunction which leads to decreased testosterone levels and an increase in LH due to loss of negative feedback. In Kallmann syndrome, failed migration of GnRH-producing neurons leads to lack of GnRH. No GnRH results in a decrease in LH, FSH, testosterone, and sperm count. Specific to Kallmann syndrome, in comparison to other causes of hypogonadotropic hypogonadism, is defects in the sensation of smell (hyposmia or anosmia). ,,
5-alpha reductase is an enzyme that converts testosterone to dihydrotestosterone. Male patients with 5-alpha reductase deficiency present with normal female or male genitalia or ambiguous genitalia at birth due to lack of dihydrotestosterone. These patients have a male internal urogenital tract (anti-Mullerian hormone is still present). At puberty, adolescents with this enzyme deficiency, who may have been raised as girls due to lack of secondary male characteristics, begin to develop male secondary sex characteristics and have primary amenorrhea. These patients will have normal testosterone and LH, low DHT, and an increased testosterone-to-DHT ratio. In contrast to 5-alpha reductase deficiency, androgen insensitivity is a condition in which patients lack functional androgen receptors resulting in under-virilization. These patients, like those with 5-alpha reductase deficiency, have a 46 XY karyotype. In contrast, however, these patients have normal female external genitalia and usually undescended testes. In adolescence, they experience primary amenorrhea and breast development but have no pubic or axillary hair and lack the deepening voice changes that occur with puberty. They will have a blind vaginal pouch and abnormal internal reproductive organs (fallopian tubes, uterus, and the upper portion of the vagina) due to the production of the Mullerian inhibiting factor. These patients will have high levels of testosterone and LH.
Impaired testosterone metabolism can occur in certain cases of congenital adrenal hyperplasia (CAH). In classic CAH (95% of cases), due to 21 hydroxylase deficiency, newborns usually present with ambiguous genitalia and later develop salt wasting, vomiting, hypotension, and acidosis. A marked increase in 17-hydroxyprogesterone is diverted towards adrenal androgen synthesis and leads to hyperandrogenism. Hyperandrogenism impairs hypothalamic sensitivity to progesterone leading to a rapid rise in GnRH synthesis and thus increased LH and FSH. Elevations in LH and FSH lead to increased gonadal steroid production (17-hydroxyprogesterone, DHEA, testosterone, LH, and FSH). Diagnosis is with adrenocorticotropic hormone stimulation test showing exaggerated 17 hydroxyprogesterone response.
Testosterone Therapy in Boys with Delayed Puberty
While boys with a constitutional delay of puberty eventually have normal activation of the hypothalamic-pituitary-gonadal axis, their sexual immaturity and relative short stature may contribute to psychosocial problems. Androgen therapy, commonly given as a four-month course of testosterone injections, provides a boost in physical growth and maturity. In addition to constitutional delay of puberty, obesity and growth hormone deficiency may cause delayed puberty. Kaplowitz conducted a retrospective study to compare responses to testosterone therapy in boys with delayed puberty from constitutional delay, obesity and possible gonadotropin deficiency.
All of the boys were 14 years of age or older when they received testosterone injections. Twenty-three had constitutional delay of puberty and were of short stature, six had obesity and were of normal stature, five had hypopituitarism and growth hormone deficiency and two had isolated gonadotropin deficiency. They were prepubertal or in early puberty according to both physical characteristics and serum testosterone levels, which were less than 40 ng per dL (1.4 nmol per L). All received a course of testosterone enanthate injections, 100 mg intramuscularly, once a month for four months.
Testosterone therapy resulted in an increase in height and weight velocity in the 23 boys with constitutional pubertal delay. Penis and testicular size also increased during treatment. The six obese boys also had an increase in penis and testicular growth. The five boys with growth hormone deficiency received growth hormone replacement in addition to testosterone injections. Two of these boys had severe gonadotropin deficiency and did not demonstrate increased maturation rates. In two boys, testicular size increased, although not as rapidly as in boys with constitutional delay of puberty.
The author concludes that monitoring the response to testosterone injections in boys with delayed puberty helps to differentiate constitutional delay of puberty from gonadotropin deficiency in boys with delayed puberty. Since a rapid growth rate requires increased androgen and growth hormone production, the response to testosterone augmentation in the boys with constitutional delayed puberty excluded the possibility of growth hormone deficiency. In the obese boys, progression of maturation may have occurred after testosterone injections because of the inhibitory effects of androgens on leptin levels, which are presumed to be inceased in obese adolescent boys. After age 10, as testosterone and gonadotropin levels increase, serum leptin levels normally decline to levels found in boys five to six years of age, suggesting that increasing testosterone levels may inhibit leptin production. The author also believes that a lack of response to four testosterone injections may be useful in identifying boys who require long-term therapy because of gonadotropin deficiency.
In an accompanying editorial, Saenger and Sandberg note that testosterone therapy in boys with delayed maturation may help increase the velocity of maturation, but there is insufficient documentation to show that the psychosocial stress from delayed maturation is severe enough to warrant intervention with testosterone injections. Most of these children have a healthy adaptation, and treatment decisions should be weighed carefully. The authors believe the psychosocial benefit of treating constitutional delay of puberty may be overstated.
Low Testosterone (Male Hypogonadism): Management and Treatment
How is low testosterone treated?
Low testosterone is treated with testosterone replacement therapy, which can be given in several different ways:
- Intramuscular injections (into a muscle), usually every 10 to 14 days;
- Testosterone patches, which are used every day and are applied to different parts of the body, including the buttocks, arms, back, and abdomen
- Testosterone gels that are applied every day to the clean dry skin of the upper back and arms (the gels require care in making sure that the hormone is not accidentally transferred to another person or partner)
- Pellets that are implanted under the skin every two months
(Oral testosterone is not approved for use in the United States.)
What are the benefits of testosterone replacement therapy?
Potential benefits of testosterone replacement therapy may include:
- In boys, avoiding problems related to delayed puberty
- Loss of fat
- Increased bone density and protection against osteoporosis
- Improved mood and sense of well-being
- Improved sexual function
- Improved mental sharpness
- Greater muscle strength and physical performance
What are the side effects of testosterone replacement therapy?
The side effects of testosterone replacement therapy include:
- Acne or oily skin
- Swelling in the ankles caused by mild fluid retention
- Stimulation of the prostate, which can cause urination symptoms such as difficulty urinating
- Breast enlargement or tenderness
- Worsening of sleep apnea (a sleep disorder that results in frequent nighttime awakenings and daytime sleepiness)
- Smaller testicles
- Skin irritation (in patients receiving topical testosterone replacement)
Laboratory abnormalities that can occur with testosterone replacement include:
- Increase in prostate-specific antigen (PSA)
- Increase in red blood cell count
- Decrease in sperm count, producing infertility (inability to have children), which is especially important in younger men who desire fertility
If you are taking hormone replacement therapy, regular follow-up appointments with your physician are important.
Guidelines suggest discussing the potential risk vs. benefit of evaluating prostate cancer risk and prostate monitoring. The doctor and patient will decide together regarding prostate cancer monitoring. For patients who choose monitoring, clinicians should assess prostate cancer risk before starting testosterone treatment, and 3 to 12 months after starting testosterone:
- PSA levels should be checked at 3, 6, and 12 months within the first year, and then every year after that.
- A digital rectal examination of the prostate should be done at 3-6 months and 1 year after beginning therapy, and then every year after that. This is recommended even for men who are not on testosterone replacement therapy, as an age-related prostate cancer screening. This usually begins at age 50.
- Hematocrit levels will be checked before testosterone therapy starts, and then on a regular basis to make sure red blood cell levels remain normal.
Who shouldn’t take testosterone replacement therapy?
Testosterone replacement therapy may cause the prostate to grow. If a man has early prostate cancer, there is concern that testosterone may stimulate the cancer’s growth. Therefore, men who have prostate cancer should not take testosterone replacement therapy. It is important for all men considering testosterone replacement therapy to undergo prostate screening before starting this therapy.
Other men who should not take testosterone replacement therapy include those who have:
- An enlarged prostate resulting in urinary symptoms (difficulty starting a urinary stream)
- A lump on their prostate that has not been evaluated
- A PSA measurement above 4
- Breast cancer
- An elevated hematocrit level (higher-than-normal number of red blood cells)
- Severe congestive heart failure
- Obstructive sleep apnea that has not been treated
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What is low testosterone?
Men who have low testosterone do not make enough of the male hormone called testosterone. This hormone allows men to produce sperm and to develop and keep normal physical male traits. Low testosterone is also called testosterone deficiency or hypogonadism.
Low testosterone can lead to problems such as loss of sex drive, muscle weakness, erection problems, infertility, and weakened bones.
What causes low testosterone?
Many things can cause this problem, such as:
- Aging. It’s normal for testosterone to decrease as you age.
- Injury to the testicles, or surgery or radiation treatment in the groin area.
- Certain medicines.
- Having a long-term medical condition, such as kidney or liver disease or obesity.
- Problems related to the pituitary gland or hypothalamus.
Low testosterone also can be present at birth.
A blood test is usually done to find out if you have low testosterone. If your doctor thinks low testosterone could be related to another medical problem, he or she may do other tests.
Since testosterone normally decreases with age, your doctor can help determine whether your symptoms are from low testosterone and whether you could benefit from treatment.
How is it treated?
Treatment may depend on the cause. Low testosterone that causes symptoms usually is treated with testosterone hormone. This is called testosterone replacement. You can get it in different ways, such as in a shot, through a patch or gel on the skin, or in a tablet you place between your cheek and gum.
Another way to raise your testosterone is through pills that you swallow. These pills aren’t testosterone. Instead they are other kinds of medicine that work well to raise testosterone levels. They include medicines such as clomiphene.
Testosterone replacement may improve your sexual desire, increase your muscle mass, and help prevent bone loss. Many men with low testosterone levels report that they feel better and have more energy while taking testosterone.
Testosterone may be used to treat some men who have erection problems.
What are the side effects and risks of treatment?
Side effects of testosterone replacement may include:
- Blisters, itching, or redness on the skin under the testosterone patch.
- Soreness or increase in the size of the breasts.
- Symptoms of an enlarged prostate, such as trouble urinating.
- Sleep apnea.
The evidence from studies isn’t clear about whether taking testosterone lowers or increases the risk of heart attack, stroke, or blood clots in the veins.
Experts don’t know for sure if taking testosterone affects the risk of prostate cancer. Your doctor may recommend regular exams and blood tests to check for problems.
Testosterone can affect your fertility. If you are trying to have a child, you may want to ask your doctor if you can take a medicine that doesn’t affect fertility.