Hypogonadism overview

# Overview
Hypogonadism is a disorder of the reproductive system which results in lack of function of the gonads (ovaries or testes). Hypogonadism is caused by several conditions which may be congenital, acquired, genetic, or malignancies. Hypogonadism may be classified on the basis of etiology and the site causing the defect into primary or secondary hypogonadism. Primary hypogonadism results from defect in the gonads themselves and it is characterized by high level of the gonadotropin hormones (FSH and LH). Secondary hypogonadism indicates a defect in pituitary gland or hypothalamus and presents with a low level of gonadotropin releasing hormone, FSH, and LH. Genetic mutations that can cause hypogonadism include ANOS 1, SOX10, SEMA3A, IL17RD and FEZF1. Other genes include KISS, GNRNH, and PROK. Hypogonadism must be differentiated from diseases that may cause delayed puberty or infertility, such as Klinefelter syndrome, Kallmann syndrome and cryptorchidism. The prevalence of hypogonadism is estimated to be 38,700 per 100,000 individual aging 45 years. The incidence of hypogonadism is 1230 per 100,000 persons. Hypogonadism affects men more than women and its prevalence increases with age. Hypogonadism has many risk factors like dyslipidemia, obesity, malignancies and alcohol intake. If hypogonadism left untreated, patients will end up with infertility and rheumatic autoimmune diseases. Hypogonadism can cause complications like gynecomastia and delay of puberty in the prepubertal patients. It can also cause depression and cardiovascular stroke in the adults. Hypogonadism usually has a good prognosis with the proper treatment. Patients with hypogonadism usually present with loss of the secondary sexual characteristics. Male patients present with infertility, loss of libido and erectile dysfunction. Female patients present with amenorrhea and loss of pubic hair. Laboratory evaluation may reveal low testosterone levels and variable FSH and LH levels according to the cause of hypogonadism whether primary or secondary. The mainstay of treatment for hypogonadism is testosterone replacement therapy and it can be administrated through different regimens injected, transdermal or buccal. In females, estrogen replacement is helpful besides testosterone.

# Historical Perspective
Hypogonadism was first reported by Dr. Maestre de San Juan in a case of small testes and loss of smelling sensation. Dr. Kallmann in 1944 identified this syndrome which was named on him after that. Dr. de Morsier reported various cases of hypogonadism with absent olfactory bulbs in the 1950s.

# Classification
Hypogonadism may be classified according to the etiological site into three subtypes primary, secondary or combined. It can also be classified according to the age into two adult and child. Based on the causes, it can be classified into acquired or congenital.

# Pathophysiology
Hypogonadism pathophysiology depends mainly on the deficiency of the testosterone hormone. Testosterone is secreted in response to stimulation from the brain to the hypothalamus which secretes the gonadotropin releasing hormones (GnRH). GnRH is responsible for secretion of FSH and LH. In males, LH stimulates the leydig cells in the testes which produce testosterone by converting the cholesterol to testosterone. In females, FSH and LH stimulate secretion of estrogen which helps in follicles maturation. Also, estrogen is involved in the ovulation process. GnRH deficiency may lead to decrease of testosterone levels and eventually causing hypogonadism. Genetic mutations have a major role in the development of hypogonadism as well as other factors. There are more than 25 gene mutations participate in the pathogenesis of hypogonadism. Genes that are responsible for Kallmann syndrome include ANOS 1, SOX10, SEMA3A, IL17RD and FEZF1. Other influencing genes are KISS, GNRNH, and PROK.

# Causes
Hypogonadism is commonly caused by congenital and acquired genetic and endocrinological conditions. Malignancies can be life threatening causes and should take priority when diagnosing the etiology.

# Differentiating Hypopituitarism from Other Diseases
Hypogonadism must be differentiated from diseases that cause delayed puberty or infertility. These diseases include congenital diseases as Klinefelter syndrome, Kallmann syndrome and cryptorchidism. The diseases include also testicular torsion and orchitis in males, polycystic ovary syndrome, pelvic inflammatory disease, and endometriosis in females.

# Epidemiology and Demographics
The prevalence of hypogonadism is estimated to be 38,700 per 100,000 individual aging 45 years. The incidence of hypogonadism is 1230 per 100,000 persons. Hypogonadism affects men more than women and its prevalence increases with age.

# Risk Factors
Common risk factors in the development of hypogonadism in men are dyslipidemia, obesity, alcohol intake, malignancies and metabolic syndrome. Common risk factors in women include nulliparity and dysmenorrhea. Other risk factors include coronary heart disease, hypertension, heart failure, and smoking.

# Screening
According to the endocrine society, screening for hypogonadism is not recommended as it is not cost-effective. Hypogonadism screening may be done in order to diagnose the disease early and provide the appropriate treatment. Screening may be done for men who present with erectile dysfunction, infertility, HIV, and young patients with osteoporosis.

# Natural History, Complications, and Prognosis
If left untreated, patients with hypogonadism will end up with infertility and rheumatic autoimmune diseases. The rheumatic autoimmune diseases include rheumatic arthritis and systemic lupus erythematosus. Complications of hypogonadism depend on age and include ambiguous genitalia in the new born, gynecomastia, and delay of puberty in the prepubertal phase. Complications include also depression and cardiovascular stroke in the adults. Prognosis of hypogonadism is good with treatment and patients can have a normal life alongside the appropriate medical therapy.

# Diagnosis

## History and Symptoms
The most common symptoms of hypogonadism in males include delayed puberty and loss of sexual characters as voice deepening and hair growth. Common symptoms include also erectile dysfunction, small testes, loss of libido and sweating. Common symptoms in females include no breast enlargement and no pubic hair. Less common symptoms include a headache, visual impairment, galactorrhea, and anorexia nervosa.

## Physical Examination
Common physical examination findings of hypogonadism include the absence of secondary sexual characteristics in both male and females. In males, pubic hair loss, no beard hair, small testicular size and congenital anomalies may be observed. In females, no axillary hair and amenorrhea are common.

## Laboratory Findings
Laboratory diagnosis consistent with cases of hypogonadism is measuring testosterone levels, gonadotropin hormones level and the semen analysis for the male patients. Testosterone level is low in cases of hypogonadism. Gonadotropin hormones level differs between the primary hypogonadism and secondary hypogonadism. The gonadotropin hormones are high in the primary causes and low in the secondary causes.

## X ray
X-ray may be performed in cases of hypogonadism only on bones to assess the bone age and the skeletal growth. A pelvic x-ray may be also needed to assess the internal genitalia and detect any masses.

## CT scan
There are no CT findings associated with hypogonadism.

## MRI scan
MRI is performed in cases of hypogonadism to evaluate the pituitary gland and hypothalamus to detect any tumors that may cause hypogonadism. It is performed in specific patients who present with visual disturbances, neurological impairments and lab findings suggestive for hypopituitarism. Possible findings may include empty sella turcica and pituitary adenomas.

## Ultrasound
Ultrasound may be helpful in females presenting with hypogonadism to evaluate the uterus or to rule out cryptorchidism in males.

## Other Diagnostic Studies
There are no other diagnostic studies for hypogonadism.

## Other imaging findings
There are no other imaging findings for hypogonadism.

# Treatment

## Medical Therapy
The mainstay of therapy for hypogonadism is the hormonal replacement therapy. Based on the endocrine society clinical guidelines, testosterone is important for the treatment of hypogonadism. Different regimens include injected, buccal and transdermal testosterone. For women, estrogen replacement therapy is important besides testosterone.

## Surgery
Surgical intervention is not recommended for the management of hypogonadism. However, in some cases of the hypogonadism which present with high risk of malignancy, gonadal tissue should be surgically removed. This is more important in genetic diseases like Turner syndrome. In males, orchiectomy is indicated if the patient has completely nonfunctioning testes.

## Prevention
There are no established methods for prevention of hypogonadism.