eMedicine Specialties > Pediatrics: General Medicine > Endocrinology
Hypogonadism
Updated: Nov 16, 2007
Introduction
Background
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.
Pathophysiology
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-releasing hormone (LHRH; also termed gonadotropin-releasing hormone [GnRH]) into the hypothalamic-pituitary portal system. Recent data suggest that a gene named KISS is important in the development of the LHRH secreting cells.1
In response to these pulses of LHRH, the anterior pituitary secretes follicle-stimulating hormone (FSH) and luteinizing hormone (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.
Frequency
International
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.
Mortality/Morbidity
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.
Race
No racial predilection has been described.
Sex
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.
Age
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.
Clinical
History
For both males and females, determining whether evidence of a genital abnormality is present at birth or determining the timing and extent of puberty is important. In addition, because Kallmann syndrome (hypogonadotropic hypogonadism and anosmia [ie, lack of a sense of smell]) is a common cause of hypogonadotropic hypogonadism, inquiring about the sense of smell is important.
- Males
- Specific issues include the presence of developmental anomalies associated with the genital system (eg, hypospadias, micropenis, cryptorchidism).
- For postpubertal males, inquire about the rate of beard growth, libido and sexual function, muscle strength, and energy levels.
- Investigate possible causes of acquired testicular failure (eg, mumps orchitis, trauma, radiation exposure of the head or testes, chemotherapy). Drugs that may interrupt testicular function include agents that interfere with testosterone synthesis, such as spironolactone, cyproterone, marijuana, heroin, and methadone.
- Females
- Ask about specific signs associated with Turner syndrome, such as lymphedema, cardiac or renal congenital anomalies, and short growth pattern.
- Determine the age of menarche. Menstrual history is important in postpubertal females.
Physical
- Males
- Evaluation of the testes 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. Before puberty, testes usually are 1-3 cm3 in volume (approximately 2 cm in length). During puberty, testes grow up to 25 cm3 in size.
- Examining the genitalia for hypospadias is the next important step. Check the scrotum to see if it is completely fused. Finally, evaluate the extent of virilization.
- Puberty should be staged using the Tanner criteria for genitalia, pubic hair, and axillary hair.
- Look for signs of Klinefelter syndrome, such as tall stature (especially if legs are disproportionately long), gynecomastia, small or soft testes, and a eunuchoid body habitus.
- Females
- Examination of the genitalia is important.
- Determine the extent of androgenization, which may be adrenal or ovarian in origin and is demonstrated in pubic and axillary hair.
- Determine the extent of estrogenization, as evidenced by breast development and maturation of the vaginal mucosa.
- Look for signs of Turner syndrome, such as short stature, webbing of the neck (eg, pterygium colli), a highly arched palate, short fourth metacarpals, widely spaced nipples, or multiple pigmented nevi.
Causes
- Hypogonadotropic hypogonadism
- CNS disorders
- Tumors
- Craniopharyngioma
- Germinoma
- Other germ cell tumors
- Hypothalamic and optic glioma
- Astrocytoma
- Pituitary tumor
- Miscellaneous causes
- Langerhans histiocytosis
- Postinfectious lesions of the CNS
- Vascular abnormalities of the CNS
- Radiation therapy
- Congenital malformations (especially associated with craniofacial anomalies)
- Head trauma
- Genetic causes (see Genetics of hypogonadotropic hypogonadism)
- Kallmann syndrome (mutation in the KAL [anosmin] gene), with hyposmia or anosmia or without anosmia
- Congenital adrenal hypoplasia (mutation in the DAX1 gene)
- Mutations in the PROP1 and HESX1 genes
- Mutations in the gene coding for the GnRH (LHRH) receptor
- Isolated LH deficiency
- Isolated FSH deficiency
- Idiopathic and genetic forms of multiple hormone deficiencies
- Chronic systemic disease and malnutrition
- Exercise-induced amenorrhea
- Miscellaneous disorders, including Prader-Willi syndrome, Laurence-Moon syndrome, Bardet-Biedl syndrome, functional gonadotropin deficiency (psychogenic amenorrhea, hypothyroidism, diabetes mellitus, Cushing syndrome), hyperprolactinemia, marijuana use, and Gaucher disease
- Hypergonadotropic hypogonadism in males
- Klinefelter syndrome
- Inactivating mutations
- LH beta subunit
- FSH beta subunit
- LH receptor
- FSH receptor
- Other causes of primary testicular failure
- Chemotherapy
- Radiation therapy
- Testicular biosynthetic defects
- Sertoli-cell-only syndrome
- LH resistance
- Anorchism and cryptorchidism
- Hypergonadotropic hypogonadism in females
- Turner syndrome
- Inactivating mutations
- LH beta subunit
- FSH beta subunit
- LH receptor
- FSH receptor
- XX and XY gonadal dysgenesis
- Familial and sporadic XX gonadal dysgenesis and its variants
- Familial and sporadic XY gonadal dysgenesis and its variants
- Other causes of primary ovarian failure
- Genetics of hypogonadotropic hypogonadism: To date, a number of genes have been identified as causes of hypogonadotropic hypogonadism. The genes include the following:
- KAL is located on the X chromosome, just below the pseudoautosomal region. An abnormality in this gene results in Kallmann syndrome, which is characterized by anosmia and hypogonadotropic hypogonadism.
- The DAX1 gene is associated with X-linked adrenal hypoplasia congenita (hypogonadotropic hypogonadism and adrenal insufficiency).
- GNRHR is the gene associated with the GnRH (LHRH) receptor.
- PC1 is the gene for prohormone convertase 1. Abnormality of this gene causes hypogonadotropic hypogonadism and defects in prohormone processing.
- In addition, mutations in the PROP1 gene have resulted in absence of several pituitary hormones, including growth hormone, thyroid-stimulating hormone, prolactin, and gonadotropins. PROP1 encodes a protein expressed in the embryonic pituitary, which is necessary for function of POU1F1 (formerly PIT1), which codes for a pituitary transcription factor.
- In addition, mutation of the gene HESX1 has been associated with septooptic dysplasia, which may include poor development of the pituitary.
More on Hypogonadism |
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| Differential Diagnoses & Workup: Hypogonadism |
| Treatment & Medication: Hypogonadism |
| Follow-up: Hypogonadism |
| References |
| Next Page » |
References
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Further Reading
Keywords
hypogonadism, ovarian failure, testicular failure, gonadal failure, eunuchoidism, primary amenorrhea, secondary amenorrhea, decreased sexual function, sparse body hair, delayed epiphyseal closure, hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, gonadotropin deficiency, Turner syndrome, Turner's syndrome, Klinefelter syndrome, Klinefelter's syndrome, infertility, sexual dysfunction, decreased muscular strength, primary hypogonadism, sexual ambiguity, Kallmann syndrome, Kallmann's syndrome, genital abnormality, hypospadias, cryptorchidism, micropenis
