Hypogonadism

Hypogonadism
Classification and external resources
ICD-10	E28..3,E29..1,E23..0
ICD-9	257.2
OMIM	146110
DiseasesDB	21057
MedlinePlus	001195
MeSH	D007006

Hypogonadism is a medical term for decreased functional activity of the gonads.^[1] Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males. The gonads, typically called testicles in males, produce hormones (testosterone, estradiol, antimullerian hormone, progesterone, inhibin B, activin) and gametes or sperm.

Symptoms

In men

Effects of low testosterone in men may include: (not all are present in any single individual)^[2]

• Poor libido (Low sexual desire)
• Fatigue (medical) always tired
• Muscle loss/atrophy
• Erectile Dysfunction
• Increasing abdominal fat
• Glucose intolerance (early diabetes)
• High Cholesterol/Lipid
• Poor sleep
• Difficulty concentrating
• Memory Loss-difficulty in choosing words in language
• Shyness
• Depression
• Anxiety
• Psychological and relationship problems
• Gynecomastia
• Hot flashes
• Decrease in growth of, or loss of, beard and body hair
• Loss of bone mass (osteoporosis)^[3]
• Irritability
• Infertility
• Shrinking of the testicles
• Decrease in firmness of testicles
• Frequent urination (polyuria) without infection; waking at night to urinate ([nocturia])
• Achy muscles
• Liquid stools
• Night sweats
• Dry skin and/or cracking nails
• Reduced Quality of Life^[4]

In women

Effects of low estrogen levels in women may include: (not all are present in any individual)^[2][5]

• Hot flashes
• Poor libido
• Infertility
• Loss of, or failure to develop, menstruation
• Loss of body hair
• Loss of bone mass (osteoporosis)
• Heart disease
• Sleep disturbances
• Symptoms of urinary bladder discomfort like frequency, urgency, frequent infections, lack of lubrication, discharge
• Shrinking of breasts
• Loss of or nonexistent sense of smell

Diagnosis

In men

Low Testosterone can be identified through a simple blood test performed by a laboratory, ordered by a physician. This test is typically ordered in the morning hours, when levels are highest, as levels can drop by as much as 13% during the day.^[6]

Normal total testosterone levels range from 300 - 1000 ng/dL^[7]

Treatment is often prescribed for total testosterone levels below 350 ng/dL.^[8] If the serum total testosterone level is between 230 and 350 ng/dL, repeating the measurement of total testosterone with sex hormone-binding globulin (SHBG) to calculate free testosterone or free testosterone by equilibrium dialysis may be helpful.

Blood testing

A position statement by The Endocrine Society has expressed dissatisfaction with the manner in which most assays for TT (Total Testosterone) and FT (Free Testosterone) are currently performed.^[9] In particular, research has questioned the validity of commonly administered assays of FT by RIA.^[9] The FAI (Free Androgen Index) has been found to be the worst predictor of Free Testosterone.^[10]

In women

Similar to men, the LH and FSH will be used, particularly in women who believe they are in menopause. These levels change during a woman's normal menstrual cycle, so the history of having ceased menstruation coupled with high levels aids the diagnosis of being menopausal. Commonly, the post-menopausal woman is not called hypogonadal if she is of typical menopausal age. Contrast with a young woman or teen, who would have hypogonadism rather than menopause. This is because hypogonadism is an abnormality, whereas menopause is a normal change in hormone levels.

Hypogonadism is often discovered during evaluation of delayed puberty, but ordinary delay, which eventually results in normal pubertal development, wherein reproductive function is termed constitutional delay. It may be discovered during an infertility evaluation in either men or women.

Treatment

Male hypogonadism is most often treated with testosterone replacement therapy (TRT) in patients who are not trying to conceive. Commonly-used testosterone replacement therapies include transdermal (through the skin) using a patch or gel, injections, or pellets. Oral testosterone is no longer used in the U.S. because it is broken down in the liver and rendered inactive; it also can cause severe liver damage. Like many hormonal therapies, changes take place over time. It may take as long as 2–3 months at optimum level to reduce the symptoms, particularly the wordfinding and cognitive dysfunction. Testosterone levels in the blood should be evaluated to ensure the increase is adequate. Levels between 500 and 700 ng/dL are considered adequate for young, healthy men from 20 to 40 years of age, but the lower edge of the normal range is poorly defined and single testosterone levels alone cannot be used to make the diagnosis. Modern treatment may start with 200 mg intramuscular testosterone, repeated every 10–14 days. Getting a blood level of testosterone on the 13th day will give a "trough" level, assisting the physician in deciding whether the correct dose is being given.^{[citation needed]}

Recently some have reported using anastrozole (Arimidex), an aromatase inhibitor used in women for breast cancer, to decrease conversion of testosterone to estrogen in men, and increase serum testosterone levels.^{[citation needed]}

While historically men with prostate cancer risk were warned against testosterone therapy, that has shown to be a myth.^[11]

Other side effects can include an elevation of the hematocrit to levels that require blood to be withdrawn (phlebotomy) to prevent complications from it being "too thick". Another is that a man may have some growth in the size of the breasts (gynecomastia), though this is relatively rare. Finally, some physicians worry that Obstructive Sleep Apnea may worsen with testosterone therapy, and should be monitored.^{[citation needed]}

Another feasible treatment alternative is human chorionic gonadotropin (hCG).^[12]

For both men and women, an alternative to testosterone replacement is Clomifene treatment which can stimulate the body to naturally increase hormone levels while avoiding infertility and other side effects as a consequence of direct hormone replacement therapy.^[13]

For women, estradiol and progesterone are replaced. Some types of fertility defects can be treated, others cannot. Some physicians will also give testosterone to women, mainly to increase libido.^{[citation needed]}

Classification

Deficiency of sex hormones can result in defective primary or secondary sexual development, or withdrawal effects (e.g., premature menopause) in adults. Defective egg or sperm development results in infertility. The term hypogonadism is usually applied to permanent rather than transient or reversible defects, and usually implies deficiency of reproductive hormones, with or without fertility defects. The term is less commonly used for infertility without hormone deficiency. There are many possible types of hypogonadism and several ways to categorize them. Hypogonadism is also categorized by endocrinologists by the level of the reproductive system that is defective.Physicians measure gonadotropins (LH and FSH) to distinguish primary from secondary hypogonadism. In primary hypogonadism the LH and/or FSH are usually elevated, meaning the problem is in the testicles, whereas in secondary hypogonadism, both are normal or low, suggesting the problem is in the brain.

Affected system

• Hypogonadism resulting from defects of the gonads is traditionally referred to as primary hypogonadism. Examples include Klinefelter syndrome and Turner syndrome. Mumps is known to cause testicular failure, and in recent years has been immunized against in the US. A varicocele can reduce hormonal production as well.

• Hypogonadism resulting from hypothalamic or pituitary defects are termed secondary hypogonadism or central hypogonadism (referring to the central nervous system).
  • Examples of Hypothalamic defects include Kallmann syndrome.
  • Examples of Pituitary defects include hypopituitarism.

• An example of a hypogonadism resulting from the lack of hormone response is androgen insensitivity syndrome, where there are inadequate receptors to bind the testosterone, resulting in a female appearance despite XY chromosomes.

Primary or secondary

• Primary - defect is inherent within the gonad: eg. Noonan syndrome, Turner syndrome (45X,0), Klinefelter syndrome (47XXY), XY females with SRY gene-immunity
• Secondary - defect lies outside of the gonad: eg. Kallmann syndrome and Polycystic ovary syndrome, also called hypogonadotropic hypogonadism.^[5] Hemochromatosis and diabetes mellitus can be causes of this as well.

Congenital vs. acquired

• Examples of congenital causes of hypogonadism, that is, causes that are present at birth:
  • Turner syndrome in females, and Klinefelter syndrome in males. It is also one of the signs of CHARGE syndrome.

• Examples of acquired causes of hypogonadism:
  • Anabolic Steroids Induced Hypogonadism (ASIH)
  • The use of androgen inhibitors such as Finasteride
  • Childhood mumps
  • Children born to mothers who had ingested the endocrine disruptor diethylstilbestrol for potential miscarriage
  • Traumatic brain injury, even in childhood.
  • In males, normal aging causes a decrease in androgens, which is sometimes called "male menopause" (also known by the coinage "manopause"), Late-Onset Hypogonadism (LOH), Andropause or Androgen Decline in the Aging Male (ADAM).

Hormones vs. fertility

Hypogonadism can involve just hormone production or just fertility, but most commonly involves both.

• Examples of hypogonadism that affect hormone production more than fertility are hypopituitarism and Kallmann syndrome; in both cases, fertility is reduced until hormones are replaced but can be achieved solely with hormone replacement.
• Examples of hypogonadism that affect fertility more than hormone production are Klinefelter syndrome and Kartagener syndrome.

Testosterone and longevity

A longitudinal (18 year) study published by The Endocrine Society and funded by the National Institute on Aging and the American Heart Association stated: Men over 50 may not live as long if they have low testosterone. The study looked at death from any cause in nearly 800 men ages 50 to 91 years who were living in a southern California community and who participated in the Rancho Bernardo Study in the 1980s. At the beginning of the study, almost one-third of these men had suboptimal blood testosterone levels for men their age. The men with low testosterone levels had a 33 percent greater risk of death during the next 18 years than the men with higher testosterone. This difference was not explained by smoking, alcohol intake, level of physical activity, or by pre-existing diseases such as diabetes or heart disease.^[14]

The new study is the second report linking the deficiency of this sex hormone with increased death from all causes over time, said study author Gail Laughlin, PhD.

References

1. ^ "hypogonadism" at Dorland's Medical Dictionary
2. ^ ^{a b} MedlinePlus Medical Encyclopedia - Hypogonadism, accessed on July 3, 2009.
3. ^ NIH Osteoporosis and Related Bone Diseases - National Research Center http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/men.asp#b
4. ^ Brooke JC & Jones TH. Low testosterone and severity of erectile dysfunction (ED) are independently associated with poor health related quality of life (HRQoL) in men with type 2 diabetes Endocrine Abstracts 25:P152; 2011, [1]
5. ^ ^{a b} MedlinePlus Medical Encyclopedia - Hypogonadotropic hypogonadism, accessed on July 3, 2009.
6. ^ Crawford, E. David; Barqawi, Al Baha; O'Donnell, Colin; Morgentaler, Abraham (2007). "The association of time of day and serum testosterone concentration in a large screening population". BJU International 100 (3): 509–13. doi:10.1111/j.1464-410X.2007.07022.x. PMID 17555474. Lay summary – UroToday (12 July 2007). 
7. ^ Cooper, Robert (January 21, 2010). "Testosterone". MedlinePlus. United States National Library of Medicine. http://www.nlm.nih.gov/MEDLINEPLUS/ency/article/003707.htm. 
8. ^ Nieschlag E, Swerdloff R, Behre HM, et al. (2006). "Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations". Journal of Andrology 27 (2): 135–7. doi:10.2164/jandrol.05047. PMID 16474020. 
9. ^ ^{a b} Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H (February 2007). "Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement". The Journal of Clinical Endocrinology and Metabolism 92 (2): 405–13. doi:10.1210/jc.2006-1864. PMID 17090633. 
10. ^ Morris PD, Malkin CJ, Channer KS, Jones TH (August 2004). "A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men". European Journal of Endocrinology 151 (2): 241–9. doi:10.1530/eje.0.1510241. PMID 15296480. 
11. ^ Morgentaler (2006). "Testosterone and prostate cancer: an historical perspective on a modern myth". European urology 50 (5): 935–9. doi:10.1016/j.eururo.2006.06.034. PMID 16875775. 
12. ^ Chudnovsky, A.; Niederberger, C. S. (2007). "Gonadotropin Therapy for Infertile Men with Hypogonadotropic Hypogonadism". Journal of Andrology 28 (5): 644–6. doi:10.2164/jandrol.107.003400. PMID 17522414. 
13. ^ Whitten, S; Nangia, A; Kolettis, P (2006). "Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate". Fertility and Sterility 86 (6): 1664–8. doi:10.1016/j.fertnstert.2006.05.042. PMID 17007848. 
14. ^ Laughlin, G. A.; Barrett-Connor, E.; Bergstrom, J. (2007). "Low Serum Testosterone and Mortality in Older Men". Journal of Clinical Endocrinology & Metabolism 93 (1): 68–75. doi:10.1210/jc.2007-1792. PMC 2190742. PMID 17911176. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2190742. Lay summary – The Endocrine Society (5 June 2008). 

External links

• GeneReview/NIH/UW entry on Hypogonadotropic Hypogonadism Overview
• NIH
• eMedicine.com
• The Pituitary Foundation