- Author: Stephen Kemp, MD, PhD; Chief Editor: George T Griffing, MD more...
Morbidity for men and women with hypogonadism includes infertility and an increased risk of osteoporosis; there is no increase in mortality.
Hypogonadotropic hypogonadism (see the image below) is one of several types of hypogonadism.
Signs and symptoms
Considerations in the evaluation of males with hypogonadism include the following:
Developmental anomalies associated with the genital system (eg, hypospadias, micropenis, and cryptorchidism) 
For postpubertal males, the rate of beard growth, libido and sexual function, muscle strength, and energy levels
Possible causes of acquired testicular failure (eg, mumps orchitis, trauma, radiation exposure of the head or testes, and chemotherapy)
Drugs that may interrupt testicular function: Including agents that interfere with testosterone synthesis, such as spironolactone, cyproterone, marijuana, heroin, and methadone
Considerations in the evaluation of females with hypogonadism include the following:
Signs associated with Turner syndrome (eg, lymphedema, cardiac or renal congenital anomalies, and short growth pattern)
Age of menarche
Considerations in the physical examination of males with hypogonadism include the following:
Evaluation of the testes: This is the most important feature of the physical examination; determine whether both testes are palpable, their position in the scrotum, and their consistency; testes size can be quantitated by comparison with testicular models (orchidometer), or their length and width may be measured
Examination of the genitalia for hypospadias
Examination of the scrotum to see if it is completely fused
Evaluation of the extent of virilization
Staging of puberty: Use the Tanner criteria for genitalia, pubic hair, and axillary hair
Examination for signs of Klinefelter syndrome (eg, tall stature, especially if the legs are disproportionately long, gynecomastia, small or soft testes, and a eunuchoid body habitus)
Considerations in the physical examination of females with hypogonadism include the following:
Examination of the genitalia is important
Determination of the extent of androgenization: May be adrenal or ovarian in origin and is demonstrated in pubic and axillary hair
Determination of the extent of estrogenization: As evidenced by breast development and maturation of the vaginal mucosa
Examination for signs of Turner syndrome (eg, short stature, webbing of the neck [such as pterygium colli], a highly arched palate, short fourth metacarpals, widely spaced nipples, or multiple pigmented nevi)
See Clinical Presentation for more detail.
The following studies may be indicated in males with hypogonadism:
Follicle-stimulating hormone (FSH) levels
Luteinizing hormone (LH) levels
Seminal fluid examination
For males after puberty, the Guidelines of the Endocrine Society require that the diagnosis of hypogonadism be based on symptoms and signs of hypogonadism plus the presence of a low testosterone level measured on at least 2 occasions.
The following studies may be indicated in females with hypogonadism:
Antiovarian antibody levels: If gonadotropin levels are elevated
Additional tests in the evaluation of patients with hypogonadism include the following:
Adrenocorticotropic hormone (ACTH) stimulation testing: In patients in whom a form of congenital adrenal hyperplasia is suspected, adrenal steroid synthesis is best evaluated by performing a cosyntropin (ACTH 1-24) stimulation test
Luteinizing-hormone releasing hormone (LHRH) stimulation testing: To distinguish between true hypogonadotropic hypogonadism and constitutional delay in growth and maturation
Testicular tissue testing: If the testes are not palpable and if it is not certain whether any testicular tissue is present, administering human chorionic gonadotropin (hCG) and measuring testosterone response may be helpful
See Workup for more detail.
The simplest and most successful treatment for males and females with either hypergonadotropic or hypogonadotropic hypogonadism is replacement of sex steroids, but the therapy does not confer fertility or, in men, stimulate testicular growth.
When fertility is desired, an alternative therapy for men with hypogonadotropic hypogonadism is administration of pulsatile LHRH or injections of hCG and FSH. (In patients with hypergonadotropic hypogonadism, fertility is not possible.)
In a 6-year European study of men being treated for hypogonadism, long-term transdermal testosterone treatment did not increase prostate-specific antigen (PSA) levels or influence prostate cancer risk.[3, 4]
Investigators used data from a 5-year, open-label extension of a 1-year trial of a transdermal testosterone patch (Testopatch) in men with hypogonadism. Study subjects wore two 60 cm2 patches, each of which delivered 2.4 mg of testosterone per day. More than 90% of patients had PSA concentrations below 2 ng/mL during the 6-year study, and no prostate cancer was found in patients over the course of the trial.
Hypogonadism manifests differently in males and in females before and after the onset of puberty. If onset is in prepubertal males and testosterone replacement is not instituted, the individual has features of eunuchoidism, which include sparse body hair, poor development of skeletal muscles, and delay in epiphyseal closure, resulting in long arms and legs. When hypogonadism occurs in postpubertal males, lack of energy and decreased sexual function are the usual concerns. In females with hypogonadism before puberty, failure to progress through puberty or primary amenorrhea is the most common presenting feature. When hypogonadism occurs in postpubertal females, secondary amenorrhea is the usual concern.
The gonad (ovary or testis) functions as part of the hypothalamic-pituitary-gonadal axis. A hypothalamic pulse generator resides in the arcuate nucleus, which releases luteinizing hormone (LH)-releasing hormone (LHRH), which is also termed gonadotropin-releasing hormone (GnRH), into the hypothalamic-pituitary portal system. Data suggest that a gene named KISS is important in the development of the LHRH-secreting cells.[6, 7]
In response to these pulses of LHRH, the anterior pituitary secretes follicle-stimulating hormone (FSH) and LH, which, in turn, stimulate gonadal activity. The increase in gonadal hormones results in lowered FSH and LH secretion at the pituitary level, completing the feedback loop. In the testes, LH stimulates Leydig cells to secrete testosterone, whereas FSH is necessary for tubular growth. In the ovaries, LH acts on theca and interstitial cells to produce progestins and androgens, and FSH acts on granulosa cells to stimulate aromatization of these precursor steroids to estrogen.
Hypogonadism may occur if the hypothalamic-pituitary-gonadal axis is interrupted at any level. Hypergonadotropic hypogonadism (primary hypogonadism) results if the gonad does not produce the amount of sex steroid sufficient to suppress secretion of LH and FSH at normal levels. Hypogonadotropic hypogonadism may result from failure of the hypothalamic LHRH pulse generator or from inability of the pituitary to respond with secretion of LH and FSH. Hypogonadotropic hypogonadism is most commonly observed as one aspect of multiple pituitary hormone deficiencies resulting from malformations (eg, septooptic dysplasia, other midline defects) or lesions of the pituitary that are acquired postnatally. In 1944, Kallmann and colleagues first described familial isolated gonadotropin deficiency. Recently, many other genetic causes for hypogonadotropic hypogonadism have been identified.
Normosmic hypogonadotropic hypogonadism, in which the sense of smell is not disrupted, has been associated with mutations in GNRH1, KISS1R, and GNRHR genes. Although their exact functions are unclear, the genes TAC3 and TACR3 have also been associated with normosmic hypogonadotropic hypogonadism. Kallmann syndrome (anosmic hypogonadotropic hypogonadism) has been associated with mutations in KAL1, FGFR1, FGF8, PROK2, and PROKR2 genes. The relationship with Kallmann syndrome is thought to be because these genes are all related to the development and migration of GnRH neurons. Mutations of an additional gene, CHD7, which has been associated with CHARGE syndrome, has also been found in patients with both normosmic or anosmic hypogonadotropic hypogonadism.
In women with hypergonadotropic hypogonadism (ie, gonadal failure), the most common cause of hypogonadism is Turner syndrome, which has an incidence of 1 case per 2,500-10,000 live births. In men with hypergonadotropic hypogonadism, the most common cause is Klinefelter syndrome, which has an incidence of 1 case per 500-1000 live births. Hypogonadotropic hypogonadism is more rare.
No racial predilection has been described.
Hypergonadotropic hypogonadism is more common in males than in females because the incidence of Klinefelter syndrome (the most common cause of primary hypogonadism in males) is higher than the incidence of Turner syndrome (the most common cause of hypogonadism in females). Incidence of hypogonadotropic hypogonadism is equal in males and females.
Hypogonadism may occur at any age; however, consequences differ according to the age at onset. If hypogonadism occurs prenatally (even if incomplete), sexual ambiguity may result. If hypogonadism occurs before puberty, puberty does not progress. If hypogonadism occurs after puberty, infertility and sexual dysfunction result.
No increase in mortality is observed in patients with hypogonadism. Morbidity for men and women includes infertility and an increased risk of osteoporosis. In women, an increased risk of severe osteoporosis is noted. In men, hypogonadism causes decreased muscle strength and sexual dysfunction.
Men and women with hypogonadism can lead a normal life with hormone replacement.
Approximately 20-25% of females with Turner syndrome have some spontaneous puberty. Spontaneous estrogenization occurs more commonly in women with mosaic karyotypes and those karyotypes with an abnormal second X chromosome, such as 46,XXiq or 46,XXip. Reports exist of women with mosaic Turner syndrome becoming pregnant without in vitro fertilization.
[Guideline] Tekgul S, Riedmiller H, Gerharz E, et al. Micropenis. Guidelines on paediatric urology. 2009 Mar. [Full Text].
[Guideline] Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Jun. 95(6):2536-59. [Medline].
Boggs W. Transdermal Testosterone Doesn't Boost PSA Levels or Prostate Cancer Risk. Medscape Medical News Jan 15, 2013. Available at http://www.medscape.com/viewarticle/777680. Accessed: January 24, 2013.
Raynaud JP, Gardette J, Rollet J, Legros JJ. Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of transdermal testosterone treatment. BJU Int. 2013 Jan 7. [Medline].
Viswanathan V, Eugster EA. Etiology and treatment of hypogonadism in adolescents. Endocrinol Metab Clin North Am. 2009 Dec. 38(4):719-38. [Medline].
Murphy KG. Kisspeptins: regulators of metastasis and the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2005 Aug. 17(8):519-25. [Medline].
Silveira LG, Noel SD, Silveira-Neto AP, et al. Mutations of the KISS1 Gene in Disorders of Puberty. J Clin Endocrinol Metab. 2010 Mar 17. [Medline].
Abdulla AB, Niloy AA, Shah TA, et al. Laurence Moon Bardet Biedl Syndrome. Mymensingh Med J. 2009 Jan. 18(1 Suppl):S124-128. [Medline].
Tucker ME. FDA OKs Natesto, First-Ever Nasal Testosterone Treatment. Medscape Medical News. May 29 2014. [Full Text].
Nainggolan L. EMA finds little evidence that testosterone ups CV risk. Medscape Medical News. October 10, 2014. [Full Text].
PRAC review does not confirm increase in heart problems with testosterone medicines. European Medicines Agency. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Testosterone_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500175213.pdf. Accessed: October 10, 2014.
Albert SG, Morley JE. Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a Systematic Review. Clin Endocrinol (Oxf). 2016 Apr 28. [Medline].
Baillargeon J, Al Snih S, Raji MA, et al. Hypogonadism and the risk of rheumatic autoimmune disease. Clin Rheumatol. 2016 Jun 20. [Medline].
Achermann JC, Gu WX, Kotlar TJ, et al. Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay. J Clin Endocrinol Metab. 1999 Dec. 84(12):4497-500. [Medline].
Bhagavath B, Podolsky RH, Ozata M, et al. Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril. 2006 Mar. 85(3):706-13. [Medline].
Bouvattier C, Tauber M, Jouret B, et al. Gonadotropin treatment of hypogonadotropic hypogonadal adolescents. J Pediatr Endocrinol Metab. 1999 Apr. 12 Suppl 1:339-44. [Medline].
Carey PO, Howards SS, Vance ML. Transdermal testosterone treatment of hypogonadal men. J Urol. 1988 Jul. 140(1):76-9. [Medline].
Kaneko N, Kawagoe S, Hiroi M. Turner's syndrome--review of the literature with reference to a successful pregnancy outcome. Gynecol Obstet Invest. 1990. 29(2):81-7. [Medline].
Lamberts SW, de Jong FH, Birkenhager JC. Evaluation of a therapeutic regimen in Cushing's disease. The predictability of the result of unilateral adrenalectomy followed by external pituitary irradiation. Acta Endocrinol (Copenh). 1977 Sep. 86(1):146-55. [Medline].
Lee PA. Disorders of puberty. Lifshitz F, ed. Pediatric Endocrinology. 3rd ed. Marcel Dekker; 1996. 175-95.
Mazer N, Bell D, Wu J, et al. Comparison of the steady-state pharmacokinetics, metabolism, and variability of a transdermal testosterone patch versus a transdermal testosterone gel in hypogonadal men. J Sex Med. 2005 Mar. 2(2):213-26. [Medline].
Muscatelli F, Strom TM, Walker AP, et al. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature. 1994 Dec 15. 372(6507):672-6. [Medline].
Nainggolan L. Five years of testosterone ameliorates metabolic syndrome in hypogonadal men. Medscape Medical News. October 28, 2013. [Full Text].
Navot D, Laufer N, Kopolovic J, et al. Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N Engl J Med. 1986 Mar 27. 314(13):806-11. [Medline].
Pozo J, Argente J. Ascertainment and treatment of delayed puberty. Horm Res. 2003. 60 Suppl 3:35-48. [Medline].
Rogol AD. Pubertal androgen therapy in boys. Pediatr Endocrinol Rev. 2005 Mar. 2(3):383-90. [Medline].
Rosenbloom AL, Almonte AS, Brown MR, et al. Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene. J Clin Endocrinol Metab. 1999 Jan. 84(1):50-7. [Medline].
Saenger P. Clinical review 48: The current status of diagnosis and therapeutic intervention in Turner's syndrome. J Clin Endocrinol Metab. 1993 Aug. 77(2):297-301. [Medline].
Seminara SB, Oliveira LM, Beranova M, et al. Genetics of hypogonadotropic hypogonadism. J Endocrinol Invest. 2000 Oct. 23(9):560-5. [Medline].
Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab. 1980 Dec. 51(6):1335-9. [Medline].
Thomas PQ, Dattani MT, Brickman JM, et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet. 2001 Jan 1. 10(1):39-45. [Medline].
Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract. 2013 Oct 15. [Medline]. [Full Text].
Tucker ME. FDA Approves Aveed Testosterone Jab, with Restrictions. Medscape Medical News. Mar 7 2014. [Full Text].