Primary hypogonadism
Congenital
1. Chromosomal disorders
(a) Klinefelter syndrome and related syndromes (such as Male 46 XX)
(b) Defects enzyme in the biosynthesis of testosterone
(c) Myotonic dystrophy
2. Developmental disorders
(a) Exposure to endocrine disruptors prenatal
(b) Cryptorchidism
(c) Anorchia due to bilateral torsion testes syndrome or missing
(d) Noonan Syndrome
Acquired
1. Orchitis
2. Mumps and other viruses
3. Infiltrative diseases (such as amyloidosis, hemochromatosis)
4. Acquired immunodeficiency syndrome (AIDS)
5. Granulomatous diseases (such as leprosy and tuberculosis)
6. Irradiation
7. Surgical lesions
8. Trauma and testicular torsion of the testicle
9. Varicocele
10. Autoimmune testicular failure
(a) Isolate
(b) Associate (as Hashimoto’s thyroiditis, diabetes mellitus type 1)
11. Drugs
(a) Anti-androgenic steroids (as flutamide, cimetidine, cyproterone, spironolactone, ketoconazole)
(b) Cytotoxic
12. Endocrine disrupting (such as insecticides, heavy metals, gossypol, environmental estrogens)
Androgen resistance syndrome
1. Testicular feminization syndrome (Morris syndrome)
2. Reifenstein syndrome
Secundary hypogodadism
Congenital
1. Multiple pituitary hormone deficiency
2. Pituitary aplasia or hypoplasia
3. Defects in the secretion or action of GnRH
(a) Mutation Kalig-1
(b) Mutation in GnRH receptor
4. Defects in the action or secretion of gonadotropins
(a) Inactivating mutations of the LH-β gene
(b) Inactivating mutations of the LH receptor gene
(c) Inactivating mutations of the FSH-β gene
(d) Mutation in DAX-1 and SF
5. GnRH deficiency
(a) Isolated (Idiopathic hypogonadotropic or hypogonadism Isolated)
(b) With anosmia (Kallmann syndrome)
(c) Associated with other abnormalities (Prader-Willi syndrome, Laurence-Moon and Bardet-Biedl syndrome, CHARGE syndrome, Rud syndrome, multiple lentigenes, basal encephalocele, cerebellar ataxia)
(d) Partial deficiency of GnRH (Fertile eunuch syndrome)
Acquired
1. Traumatic Brain Injury
2. Post-Radiation CNS (central nervous system), post-surgery, pituitary infarction, carotid aneurysm
3. Neoplasms
(a) Pituitary Adenomas: prolactinomas, nonfunctioning adenomas, others adenomas
(b) Craniopharyngioma, germinomas, gliomas, lymphomas
4. Autoimmune hypophysitis
5. Functional disorders: anorexia nervosa, dysfunction secondary to stress or other systemic diseases
6. Infiltrative disease: sarcoidosis, histiocytosis cells Langhans, hemochromatosis
7. Infectious diseases: tuberculosis, histoplasmosis, abscesses
8. Drugs
9. Endocrine disrupting
Combined hypogonadism
1. Aging
2. Alcoholism
3. Hemochromatosis
4. Sickle cell anemia
5. Congenital adrenal hypoplasia (mutation of DAX-1)
6. Endocrine disrupting
Secondary hypogonadism is usually associated with similar decreases in sperm and testosterone production. This occurs because the reduction in LH secretion promotes a reduction of testosterone production in the testes and, consequently, of intratesticular testosterone (primary hormonal stimulus for the production of sperm). In primary hypogonadism may be a decrease in spermatogenesis in major damage in the cells of the seminiferous tubules (Sertoli cells) than in Leydig cells. When this occurs, the subjects may present LH and testosterone levels normal, even with a number of ejaculated sperm very low or near zero. In these cases, FSH levels will meet high.
In cases of secondary hypogonadism also there is less susceptibility to the occurrence of gynecomastia, probably due to normal or low levels of FSH and LH which do not stimulate aromatase testicular, not increasing the conversion of testosterone to estradiol.
Causes of Hypogonadism
Primary Hypogonadism (Hypergonadotropic)
Congenital Causes
Klinefelter Syndrome (KS)
The Klinefelter syndrome is the most common sex chromosomal disorder in men, affecting one in every 660 children born alive [7]. It was first described in 1942. KS has a genetic background, with characteristics involving various specialties as embryology, pediatrics, endocrinology, cardiology, psychology, psychiatry, urology, and epidemiology.
Genetic inheritance is the extra X chromosome, which can be inherited from either parent. Most genes undergo additional X inactivation, but some may escape and serve as a genetic cause of the syndrome. Of these genes, the one that has been clearly shown to influence the phenotype of KS was short-stature home box-containing gene on chromosome X (SHOX) located pseudoautosomal region 1 in Xp. The haploinsufficiency of SHOX gene has been implicated in growth retardation and bone abnormalities in Turner syndrome and Leri-Weill of discondrosteose and is also implicated in the growth accelerated slightly in KS [8]. The karyotype more frequent in men with Klinefelter syndrome is 47, XXY (93 %) but were reported karyotypes 46, XY/47, XXY; 48, XXXY; 48, XXYY; and 49, XXXXY [7].
KS is commonly under diagnosed or is diagnosed late. Most men with KS live without a diagnosis. Boys with KS are likely to receive a diagnosis during evaluation for developmental delay and behavioral issues. Men with KS usually call attention during evaluation for infertility or hypogonadism. Only 25 % of cases are diagnosed and the average age of diagnosis is 30 years. A recent Australian study found a prevalence of 223 cases per 100,000 live births boys [9], proposing an increase in the prevalence observed in several previous studies [10] and suggesting that she should differ between populations.
KS is associated with an increased morbidity resulting in loss of life, an increase in mortality due to various diseases. Large epidemiological studies in KS were performed in two main cohorts: the British study [11] and Danish [12]. Together these studies show that the expected lifetime was reduced by 1.5–2 years, with increased mortality various diseases including diabetes, pulmonary disease, epilepsy, cerebrovascular disease, and vascular insufficiency of the intestine. In both studies, mortality among men with KS was significantly greater (hazard ratio: 1.9) and remained so after adjustment for social cohesion and education level (hazard ratio: 1.5), indicating that socioeconomic parameters can explain some but not all excess mortality in KS.
The main findings of KS are small testes, hypergonadotropic hypogonadism and cognitive impairment. Other abnormalities are associated with KS and its frequency is varied (Table 15.2) [7].
Table 15.2
Abnormalities associated with Klinefelter syndrome
Feature | Frequency (%) |
|---|---|
Infertility (adults) | 91–99 |
Small testes (both testes <6 mL) | >95 |
Increased gonadotropin | >95 |
Azoospermia (adults) | >95 |
Commitment to learning (children) | >75 |
Decreased testosterone | 63–85 |
Decreased facial hair (adults) | 60–80 |
Decreased pubic hair (adults) | 30–60 |
Gynecomastia (teens/adults) | 38–75 |
Delay in speech development (children) | 40 |
Increase height (prepubertal/adults) | 30 |
Adiposity (adults) | 50 |
Metabolic syndrome (adults) | 46 |
Osteopenia (adults) | 5–40 |
Diabetes mellitus type 2 | 10–39 |
Cryptorchidism | 27–37 |
Reduced penis size (children) | 10–25 |
Psychiatric disorders (children) | 25 |
Congenital malformations, ogival palate, inguinal hernia | 18 |
Osteoporosis (adults) | 10 |
Mitral valve prolapse (adults) | 0–55 |
Breast cancer (adults) | Increased risk (50 times) |
Mediastinum cancer (children) | Increased risk (500 times) |
Fractures | Increased risk (2–40 times) |
Azoospermia is found in the vast majority of men with KS who have the karyotype 47, XXY. The mechanism by which an extra X chromosome causes infertile patients is not well known. Men with germ cell mosaics can present in their testicles, especially at a younger age. The testicular histology in men with KS shows hyalinization of seminiferous tubules and absence of spermatogenesis. Patients with mosaics may show normal-sized testes and spermatogenesis in puberty. However, the progressive degeneration and hyalinization of seminiferous tubules occur soon after puberty. Therapeutic advances with the use of ICSI (Intracytoplasmic Sperm Injection) allow men 47, XXY azoospermic can achieve biological fatherhood [13].
The behavioral phenotype of KS is characterized by dysfunction of language, executive and psychomotor impairment and socio-emotional. Boys with KS often need speech therapy treatment, and many suffer from learning difficulties and may benefit from special education. The prevalence of schizophrenia, attention deficit hyperactivity disorder, autism spectrum disorders, and problems with mood regulation is increased. Neuroimaging studies of children and adults with KS show increases in the volume of gray matter regions of sensorimotor and parietoccipital, as well as significant reductions in the amygdale, hippocampus, insular, temporal and inferior frontal volumes of gray matter [14].
Hypogonadism in KS may lead to changes in body composition and risk of developing metabolic syndrome and diabetes type 2. Medical treatment is mainly testosterone replacement therapy to relieve acute and long-term hypogonadism, as well as treatment or prevention of comorbidities.
Other Chromosomal Abnormalities
Other chromosomal abnormalities that result in testicular hypo function were reported, including rare diseases 46, XY/XO and 47, XYY. The karyotype 46, XY/XO leads to a syndrome characterized by short-stature and other typical features of Turner syndrome. The gonad digenesis varies from the normal testes. The risk of gonadoblastoma is about 20 % if digenesis. Gonadectomy should therefore be conducted in these patients [15, 16]. The karyotype 47, XXY was initially associated with hypogonadism, but other reports have not confirmed this relationship further. Micro deletions specific regions of the long arm of chromosome Y can be detected in approximately 20 % of men with severe oligospermia or azoospermia. Some of these men have no other testicular lesions, but others have cryptorchidism [17].
Disorders of Androgen Synthesis
Mutations in genes encoding the enzymes necessary for the biosynthesis of testosterone may result in a decrease in their serum. The rare mutations found are enzyme cleavage of the side chain of cholesterol, 3β-hydroxysteroid dehydrogenase, and 17α-hydroxylase (present in the adrenals and testes) and 17β-hydroxysteroid dehydrogenase (present only in the testes). Depending on the degree of mutation meet differing degrees of fetal virilization [20].
Mutation in FSH and LH Genes
Changes in LH and FSH receptors are rare causes of primary hypogonadism. The mutation in the FSH receptor induces sperm count variable which tend to be generally low and concentrations of inhibin B and FSH levels. Mutations in LH receptor results in hypoplasia and Leydig cell testosterone deficiency in the first trimester in utero, resulting in different degrees of DDS (disorder of sexual development) [21–23].
Cryptorchidism
Cryptorchidism refers to topics that are not testicles in the scrotum. The main sites are found: inguinal canal and abdominal cavity. It is necessary to differentiate between the possible crypt orchid testes and testicles shrink, that manipulation, return to the scrotum normally. Cryptorchidism can affect one or both testes. If only one is affected testes, sperm count is subnormal in 30 % of cases (and the concentration of FSH is slightly raised), suggesting that even in the presence of a testes topic, this may present different degrees of testicular dysfunction. If both testes are cryptorchid, sperm count is usually severely impaired and serum testosterone may also be reduced. The gonadoblastoma risk also increases if the testicle is not in its normal position [24, 25].
Congenital Anorchia
Congenital anorchia occurs in disorders (after 20 weeks of gestation) that lead to testes regression. The male sex differentiation at birth is normal, but the testes are absent and hypogonadism in general is important [26]. The diagnosis is confirmed after anorchia full search of imaging studies (both in scrotal, and in the abdominal cavity) and, if necessary, laparotomy. There are case reports that testosterone treatment in adult men with congenital anorchia and micropenis and can lead to increased penile.
Acquired Causes
Varicocele
Damage to the seminiferous tubules due to varicosity of the venous plexus within the scrotum has been considered a possible cause of male infertility. Current data are conflicting about the real benefit of varicocele correction in relation to fertility [27].
Orchitis
Several infections may be associated with testicular damage. The most common cause is mumps and orchitis is a frequent manifestation occurs when adulthood. The incidence has decreased due to the vaccination of the population. The involvement of testicular mumps causes increased painful testicles, followed by atrophy. The seminiferous tubules are often severely affected, often resulting in infertility, especially when both testicles are involved. The Leydig cells can also be damaged, resulting in decreased production of testosterone.
Chronic Diseases
Gonadal dysfunction is a common finding in men with chronic kidney disease (CKD) and end-stage disease. Testosterone deficiency generally accompanied by elevated serum gonadotropin is present in 26–66 % of men with varying degrees of renal impairment. Uremia-associated hypogonadism is multifactorial in origin, and rarely improves with the onset of dialysis, although usually normalizes after renal transplantation. While there are encouraging data suggesting benefits of testosterone replacement therapy for CKD patients, more studies are needed regarding the safety and efficacy of therapeutic [28].
The gonadal function requires a normal liver function. It is well known that the clinical symptoms of hypogonadism are common in patients with liver cirrhosis. The pathogenesis of hypogonadism in cirrhotic patients is complex and not well explained. It involves both a gonadal dysfunction as a disturbance centrally [29]. Hypogonadism is a potential complication of hemochromatosis, usually seen in patients with severe iron overload and liver cirrhosis [30].
Other infiltrative or granulomatous disease may promote primary gonadal failure, varying clinics demonstrations and testicular dysfunction according to the degree of involvement of the underlying disease. Examples are tuberculosis, leprosy, among others.
HIV Infection
Men who have HIV may be hypogonadism varying degrees. The premature decline of serum testosterone is common (16 %) among young men and middle-aged HIV-infected and is associated with inappropriately low or normal LH and accumulation of visceral adipose tissue. Testosterone deficiency occurs in young people infected with HIV and may be regarded as a process of accelerated or premature aging. The role of HIV and/or treatment of HIV infection have yet to be elucidated [31]. The frequency of hypogonadism and its severity appear to have decreased since the introduction of antiretroviral therapy.
Irradiation
The direct radiation to the testes, as the treatment for leukemia, can damage them. Even when radiation is indirect, damage may occur in the seminiferous tubules. The degree of damage is proportional to the amount of radiation exposure. Radioactive iodine may cause a decrease in sperm count when the doses administered are high for treatment of differentiated thyroid carcinoma.
Gonadal Toxicity of Cancer Chemotherapy
The number of surviving young men cancer has increased dramatically over the past 20 years as a result of early detection and better treatment protocols for cancer. Over 75 % of cancer patients diagnosed in youth are long-term survivors.
The gonadal dysfunction has emerged as an important long-term complication of cancer chemotherapy, especially in young patients with hematological malignancies and testicular. Infertility can be a significant issue for many cancer survivors. The male hypogonadism after chemotherapy may contribute to fatigue, sexual dysfunction, irritability, loss of lean mass, and osteopenia. Quality of life and recovery from cancer treatment is worsened by this clinical.
Cytotoxic chemotherapy might cause injury gonadal, and the nature and extent of the damage depends on the drug, the dose received and age of the patient. Many drugs are toxics (Table 15.3) including procarbazine, cisplatin, and alkylating drugs such as cyclophosphamide, melphalan, chlorambucil. However, all chemotherapeutic drugs can cause damage to gonadal function [32]. The relative contribution of each individual drug can be difficult to determine because most treatments are conducted with multiple drug regimens [33].
Table 15.3
Estimated risk of gonadal dysfunction with cytotoxic agents
High risk | Medium risk | Low risk |
|---|---|---|
Cyclophosphamide | Cisplatin | Vincristine |
Ifosfamide | Carboplatin | Methotrexate |
Chlormethine | Doxorubicin | Dactinomycin |
Busulfan | BEP | Bleomycin |
Melphalan | ABVD | Mercaptopurine |
Procarbazine | Vinblastine | |
Chlorambucil | ||
MOPP |
Trauma and Torsion of Testes
Any trauma in the testes may be sufficient to damage both the seminiferous tubules as Leydig cells. The testicular torsion is one of the most common reasons for the loss of a testicle before puberty. The torsion of testes is a twist in the spermatic cord, which results in severe loss of blood to the testes. The loss of the testes can occur due to lack of blood if the twist is not reverted spontaneously or surgically corrected within a few hours. The degree of damage depends on the length of twist. Twist that lasts more than 8 h can promote enough damage to decrease the sperm count. Even when the twist involves only one testicle, both testicles may be damaged, it is not clear how this can occur [34–36].
Medications
Ketoconazole directly inhibits the biosynthesis of testosterone, thereby causing there is deficiency in the production [37]. Chronic use of glucocorticoids can also decrease testosterone levels in about one-third of individuals. The mechanism is not clear, but the inhibition can occur in both testes and pituitary gland [38, 39].
Autoimmune Testicular Failure
It may occur in isolation or as a manifestation of polyglandular autoimmune syndrome. Should be considered in all patients with other concomitant autoimmune diseases [40].
Secundary Hypogonadism (Hypogonadotropic)
Congenital Causes
The etiology of congenital gonadotropin dysfunction is rare. Clinical findings vary among individuals mainly due to the time of onset of dysfunction of gonadotropins. Sexual differentiation is normal because testosterone secretion by Leydig cells in fetal first trimester of pregnancy is dependent stimulation of placental hCG. The penile development occurs primarily during the third trimester of pregnancy, and is often subnormal because testicular testosterone secretion at this stage is dependent on LH secretion fetal which is also subnormal. This results in many cases in micropenis. The linear growth in childhood is normal, deficits occurring only when associated with deficiency in the production of growth hormone or thyroid hormone. Most diagnoses are made during puberty. This can initiate and submit slowing in its evolution, becoming in many cases incomplete. Some patients, depending on the degree of gonadotropin deficiency, delayed puberty may present or absent [41].
Isolated Hypogonadotropic Hypogonadism
It is characterized by isolated deficiency of gonadotropins, without changes in smell and due to deficient secretion of GnRH, GnRH receptor mutation or mutations of β fractions of LH or FSH. Several genetic mutations may be involved in the production process, hormonal secretion or action (Table 15.4). Many cases remain of unknown etiology [42, 43].
Gene | Product | Function | Clinical |
|---|---|---|---|
CHD7 | Protein linker of cromodomínio-type DNA helicase-7 | Development of the neural crest, protein bound to DNA | CHARGE syndrome—semicircular canal aplasia, hypoplasia of the olfactory bulb, GH deficiency, hypothyroidism, congenital malformations that include hypogonadotropic hypogonadism (with micropenis and/or cryptorchidism) |
DAX1/NR0B1A | Gene 1 of sex reversal | Development of adrenal, secretion of gonadotropins control | Adrenal hypoplasia congenital X-linked (primary adrenal insufficiency that is expressed in the early stages of life) |
FGF8 | Fibroblast growth factor type 8 | FGFR1 Binder/migration of GnRH neurons | Kallmann syndrome |
FGFR1 | Receptor type 1 fibroblast growth factor (FGF receptor 1) | Migration of GnRH neurons | Kallmann syndrome |
FSHβ | Β subunit of FSH | Binder receptor FSH | Isolated FSH deficiency (azoospermia, small testes in soft and undetectable serum FSH) |
GnRH1 | Pre hormone GnRH | GnRH synthesis and cell signaling | Isolated hypogonadotropic hypogonadism |
GnRHR | GnRH receptor | Synthesis of LH and FSH | Isolated hypogonadotropic hypogonadism, LH-isolated deficiency (partial mutations) |
GPR54/Kiss1R | Receptor 1 of Kisspeptin | Stimulation of secretion of GnRH | Isolated hypogonadotropic hypogonadism with attenuated LH response to exogenous GnRH stimulation |
HESX-1 | Homeobox protein ANS | Marking the previous visceral endoderm embryo | Syndrome of septo-optic dysplasia (optic nerve hypoplasia, radiological changes of online medical and hypoplastic anterior pituitary (hypopituitarism with neuro ectopic posterior pituitary) and Pickardt-Fahlbush syndrome |
HS6ST1 | 6-O-sulfotransferase heparin sulfate | Catalyzes transfer of the sulfate at position-6 in the biogenesis of heparin sulfate | Hypogonadotropic hypogonadism |
KAL1 | Anosmin-1 | Cell adhesion glycoprotein (expressed in embryonic development in olfactory bulb, cerebellum, spinal cord, kidney, and retina), migration of GnRH neurons | Kallmann Syndrome |
LEP | Leptin | Hormone regulating food intake, energy expenditure, and hypothalamic reproductive function | Homozygous mutation in the leptin exhibit morbid obesity and hypogonadism (apparently of hypothalamic origin) |
LEPR | Leptin Receptor | Membrane receptor | Morbid obesity and hypogonadism (apparently of hypothalamic origin) |
LHX3 | Transcription factor required for the development of pituitary | Hypopituitarism (corticotrophic preserving function) associated with limitation of neck rotation (rigid cervical spine), elevated and anteverted shoulders | |
LHβ | Β subunit of LH | Binder receptor LH | Isolated FSH deficiency (fertile eunuch syndrome—deficient production of testosterone associated with varying degrees of spermatogenesis) |
NELF | Factor nasal embryonic LHRH | Neuronal migration | Hypogonadotropic hypogonadism |
PROK2 | Type 2 prokineticin | Migration of GnRH neurons | Kallmann Syndrome |
PROKR2 | Receptor Type 2 prokineticin | Migration of GnRH neurons | Kallmann Syndrome |
TAC3 | Neurokinin B | Binder TACR3, Stimulates GnRH secretion | Hypogonadotropic hypogonadism |
TAC3R | Neurokinin B receptor | Stimulates the secretion of GnRH | Hypogonadotropic hypogonadism |
WDR11 | Protein WD | Interaction with transcription factor EMX1/GnRH neuronal migration | Hypogonadotropic hypogonadism |
Kallmann Syndrome
Kallmann syndrome is characterized by hypogonadotropic hypogonadism and another congenital abnormality not gonadal, including anosmia or hyposmia, red-green daltonism, midline facial defects, abnormalities of the urogenital tract, synkinesis (mirror movements), and sensorineural hearing loss. Hypogonadism is due to deficient secretion of GnRH due to defects in the migration of GnRH-secreting neurons that have the same embryological origin those olfactory neurons. Most cases are sporadic, but there may be a familial transmission (X-linked inheritance is autosomal dominant or recessive). Studies have shown mutations in genes encoding several adhesion molecules on the cell surface, receptors or necessary for the migration of neurons, such as fibroblast growth factor receptor 1 (also called KAL1) procineticina-2 (PROK2) and its receptor (PROKR-2). These mutations together represent less than half of the cases described [22, 23, 42, 44].
Laurence-Moon and Bardet-Biedl Syndrome
Acquired Causes
Hypogonadotropic hypogonadism can be caused by any disease that interferes with the hypothalamic–pituitary axis. The mechanisms that may be involved (one or more) are hypothalamic disorders (impair the GnRH secretion), disorders of the pituitary stalk (interfere with the passage of GnRH into the pituitary gland) and pituitary disorders (directly decrease the secretion of LH and FSH).
Disorders of Gonadotropin Secretion
Hyperprolactinemia
Hyperprolactinemia due to any cause can suppress gonadotropin secretion and thus testicular function [48]. Hypogonadism is reversible with normalization of the prolactin.
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