What are the other Names for this Condition? (Also known as/Synonyms) 

• Gonadal Failure
• Primary Hypogonadism
• Secondary Hypogonadism

What is Hypogonadism? (Definition/Background Information)

• Hypogonadism is the failure of the gonads to produce sex hormones in the body; either very little or no hormones may be produced. The gonads are the primary reproductive glands called the testes in males and ovaries in females, respectively
  • In males, there is a failure of the testes to produce the sex hormone testosterone
  • In females, there is failure of the ovaries to produce the sex hormone estrogen
• As a result of the lack of these sex hormones, various functional and metabolic health issues occur, depending on the age and gender of the affected individual. These may include reduced sexual function and infertility in both men and women
• The cause of Hypogonadism may include a variety of factors, including genetic disorders, malignancies, infections, use of certain medications, and advancing age. Any condition affecting the function of the pituitary gland and/or hypothalamus (in the brain) can also result in Hypogonadism
• Prenatal Hypogonadism can cause sexual ambiguity. If Hypogonadism is noted before puberty (around 13 years), then pubertal development (such as menstruation onset in girls) is disrupted. If Hypogonadism is noted after puberty, then sexual function is affected, and infertility is the most common and significant complication
• The treatment of Hypogonadism is directed towards replacing the hormones and treating the underlying cause. The prognosis of the condition generally depends upon the severity of the underlying causative condition/factor

The following two main types of Hypogonadism are described:

• Hypogonadotropic Hypogonadism, or Secondary Hypogonadism (also termed Central Hypogonadism), due to failure of the hypothalamus in releasing the luteinizing-hormone releasing hormone (LHRH) or pituitary gland failure to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
• Hypergonadotropic Hypogonadism, or Primary Hypogonadism, which arises from the failure of the gonads. Here, the gonad does not produce the amount of sex steroid sufficient to suppress the secretion of LH and FSH at normal levels

Who gets Hypogonadism? (Age and Sex Distribution)

• Depending on the underlying cause of Hypogonadism, the condition can be manifested in any age group, ranging from birth to old age
  • The most common cause of Hypergonadotropic Hypogonadism in females is Turner syndrome; the incidence rate is 1 in 2,500 to 1 in 10,000 live births
  • The most common cause of Hypergonadotropic Hypogonadism in males is Klinefelter syndrome; the incidence rate is 1 in 500 to 1,000 live births
• Since more cases of Klinefelter syndrome than Turner syndrome are noted, Hypergonadotropic Hypogonadism is more common in males than females
• Hypogonadotropic Hypogonadism is generally rare and occurs in both genders fairly equally
• The condition is commonly observed worldwide irrespective of any specific race or ethnicity

What are the Risk Factors for Hypogonadism? (Predisposing Factors)

There are several risk factors for Hypogonadism that may vary depending on whether the condition is primary or secondary and if the affected individual is a male or female. Accordingly, the predisposing factors may broadly include:

• Chromosomal abnormalities and genetic mutations affecting the gonads may result in Hypogonadism. Some of these disorders commonly include:
  • Klinefelter’s syndrome (in boys)
  • Turner’s syndrome (in girls)
• Advancing age: In both men and women, as they age, the gonads start to produce less sex hormones
• HIV/AIDS infection in any age group can result in damage to gonadal function
• Malignancies that affect the gonads resulting in hypofunction (decreased function); also, benign tumors and cancers that affect the brain (particularly the hypothalamic region or pituitary gland)
• Use of certain medications such as opioids and steroids
• Trauma to the gonads can cause temporary or permanent damage
• Morbid obesity
• Medical conditions causing gonadal dysfunction, and therefore Hypogonadism, include:
  • Hemochromatosis: A condition that develops due to iron overload secondary to frequent blood transfusions
  • Diabetes: A condition resulting in a lack of insulin or resistance to its effect. Insulin is a hormone which controls the blood sugar levels in the body
  • Cystic fibrosis (CF): A condition which causes the gonads to have impaired secretion ability
  • Polycystic ovarian disease: In women, a condition wherein the ovaries develop cysts can lead to ovarian malfunction

It is important to note that having a risk factor does not mean one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Hypogonadism? (Etiology)

Gonadal activity (testes or ovaries) is governed by the proper functioning of the pituitary gland and the hypothalamus and the secretion of hormones. Any disruption in the body from several factors can cause Hypogonadism.

The cause of Hypogonadism can be termed primary or secondary. 

• When the cause of Hypogonadism directly involves the testes or ovary, the condition is termed Primary Hypogonadism (or Hypergonadotropic Hypogonadism)
• When Hypogonadism develops as the result of an underlying disease, disorder, tumor, or infection affecting the pituitary gland or hypothalamus region, it is termed Secondary Hypogonadism (or Hypogonadotropic Hypogonadism)

The causes of Hypergonadotropic Hypogonadism in males:

• Absence of one or both testes (anorchism)
• Cancer treatments, including chemotherapy and radiation therapy (to the genital region)
• Gonadal dysgenesis (congenital developmental disorder)
• Inactivating mutation
• Klinefelter syndrome
• Ovotesticular disorder of sex development (rarely)
• Sertoli-cell-only syndrome
• Surgical removal of the testes in males (gonadectomy)
• Testicular biosynthetic defects
• Testicular resistance to luteinizing hormone
• Undescended testes (cryptorchidism)
• Testicular failure from mumps, orchitis (testicular inflammation), trauma, or frequent blood transfusions

The causes of Hypergonadotropic Hypogonadism in females:

• Autoimmune oophoritis
• Cancer treatments, including chemotherapy and radiation therapy (to the genital region)
• Follicle-stimulating hormone (FSH) receptor gene mutations
• Galactosemia
• Glycoprotein syndrome type 1
• Gonadotropin-resistant ovary syndrome
• Inactivating mutations
• Noonan syndrome
• Polycystic ovarian disease
• Premature menopause
• Resistance to luteinizing hormone (LH) or human chorionic gonadotropin (hCG)
• Turner syndrome
• XX and XY gonadal dysgenesis

Hypogonadotropic hypogonadism causes may include:

• CNS tumors affecting the pituitary gland and/or hypothalamus region of the brain, such as:
  • Astrocytoma
  • Craniopharyngioma
  • Germinoma and other germ cell tumors
  • Hypothalamic glioma
  • Optic glioma
  • Pituitary tumor
• CNS vascular abnormalities
• Genetic disorders:
  • Bardet-Biedl syndrome
  • Gaucher disease
  • Isolated follicle-stimulating hormone (FSH) deficiency
  • Isolated luteinizing hormone (LH) deficiency
  • Kallmann syndrome
  • Laurence-Moon syndrome
  • Prader-Willi syndrome
  • Septo-optic dysplasia
• Langerhans histiocytosis
• Acquired conditions such as:
  • Cushing syndrome
  • Exercise-induced hypogonadism
  • HIV infection and AIDS
  • Hyperprolactinemia
  • Malnutrition
  • Morbid obesity
  • Psychogenic hypogonadism
  • Surgery to the CNS region
  • Trauma to the head
  • Type II diabetes
  • Use of certain medications (opioids and steroids)
• Several genes have been implicated as causing Hypogonadotropic Hypogonadism

Testicular abnormality: In male babies, when they are inside the womb, the testicles are located in the belly. Shortly after birth, they descend into the scrotal sacs outside the body. When the testes remain in the belly, the temperature in the belly is too high for the testes to function normally. This can lead to Hypogonadism. 

• Some chromosomal abnormalities that can lead to Hypogonadism include:
  • Congenital androgen insensitivity: A condition in which there is resistance to male hormones and their effects. The external genitalia may be ambiguous and appear like that of a female in an individual with the genetic makeup of a male
  • Klinefelter’s syndrome: In this condition, males have an extra X chromosome. A normal male has a genetic makeup 46XY. In Klinefelter’s syndrome, the genetic make-up is 47,XXY. This extra X chromosome gives the males more feminine features. They have small testicles that do not produce testosterone sufficiently. The sperm count is also low, and the males are usually infertile
  • Cystic fibrosis: An inherited genetic defect in which there is an abnormality of the lining hair-like projections that help move secretions within the gonadal system. In males, the secretions are abnormally thick and mucus-rich, making it difficult for sperm to travel
  • Kartagener syndrome is a condition similar to cystic fibrosis. However, in addition to the abnormal mucus secretions, certain internal organs, such as the lungs and the heart, are located in the chest in a reverse manner
  • Turner’s syndrome: In this condition, due to a missing X chromosome in a girl, the ovaries fail to develop normally (termed streak ovaries). Girls born with this condition are usually short-statured, have short necks and cardiac defects
• Infection: Viruses causing mumps, HIV infection, and AIDS can affect the testes, resulting in inflammation and decreased functional ability
• Cancers: Cancerous cells can affect the gonads, causing low hormone production. Also, chemotherapy or radiation therapy administered to cancer patients can destroy the rapidly dividing cells of the gonads
• Polycystic ovarian syndrome (PCOS): In women with PCOS, the ovaries contain numerous cysts. Excess androgens circulating in the bloodstream give rise to masculine features, including acne and excess body and facial hair. Also, the ovaries fail to ovulate. Women with this condition can have irregular menstrual periods and are sometimes infertile
• Use of opioids and steroidal medication: The body recognizes these drugs as sex hormones, so the body no longer sends stimulatory signals to the gonads to produce the sex hormones
• Trauma to the abdomen or the testes can harm the tissues of the gonads, causing it to hypofunction
• Obesity: Being obese can lead to the gonadal hypofunction. In the body, the fatty tissues produce estrogen. This excess estrogen confuses the body’s hormone regulatory system, and there are fewer signals sent to the gonads, as the body senses the hormones in excess quantities, resulting in hyperfunctioning of the gonads
• Some medical conditions, such as hemochromatosis and diabetes, can cause the gonads to malfunction. In hemochromatosis, there is an excess iron load secondary to frequent blood transfusions. All this excess iron gets deposited in various organs, and if deposited in the gonads, it leads to a decrease in their function
• Ageing: In both men and women, as they age, the gonads start to produce less sex hormone
• Pituitary gland hypofunction: Sometimes, the function of the pituitary gland may be affected, causing it to send fewer stimulatory hormone signals to the gonads.
• Hypothalamic hypofunction: If the function of the hypothalamus in the brain is affected, then the hormones, called releasing hormones, are not sent out from it. The releasing hormones usually cause stimulatory signal hormones to be released from the pituitary gland, which in turn acts on the gonads, stimulating them to produce the sex hormones. In a condition called Kallman syndrome, there is hypofunctioning of the hypothalamus, leading to gonadal hypofunction

What are the Signs and Symptoms of Hypogonadism?

Hypogonadism can present with a wide variety of signs and symptoms. The associated presentations of the underlying condition (syndrome/genetic condition/malignancy) may also be noted, if any. The age of onset of Hypogonadism can be varied, resulting in different sets of signs and symptoms in males and females.

In females, the following may be noted:

• If Hypogonadism presents before puberty, menstruation in girls is affected. They will also have reduced height, and breast development will be affected
• Postpubertal feature - absence of menses for 6 months or more (secondary amenorrhea)
• If Hypogonadism develops in a woman later in life, menstruation usually ceases, and there may be a lack of libido. Conceiving children is also difficult due to reduced fertility
• Towards middle age (50-52 years), a woman’s gonads typically start to decrease in their function, termed menopause

In males, the following may be noted:

• In pre-pubertal boys, Hypogonadism can cause a reduction in muscle development and affect their height. Often, boys fail to reach the standard height for their age. They usually lack a moustache and beard with decreased body hair. The size of the penis may be small
• In men, Hypogonadism can present with several metabolic and growth dysfunctionalities 
• If Hypogonadism presents later in men, as they age, then body hair gets reduced, and there is a decrease in libido. Also, men may present with breast enlargement
• Loss of weight and signs of depression may also be observed

How is Hypogonadism Diagnosed?

Hypogonadism may be diagnosed via the following tests and exams:

• Complete physical examination and medical history evaluation (including family history)
• Assessment of presenting signs and symptoms

Evaluation in males may include some of the following tools:

• Genital anomalies of development
• Post-puberty, checking for the rate of beard growth, muscle strength, sexual function, and sexual energy levels
• Medical history evaluation for acquired and congenital conditions causing Hypogonadism, especially Klinefelter syndrome
• Medication use that may interfere with testicular function
• Substance abuse (heroin or marijuana) that may interfere with the secretion of gonadotropin
• Physical exam of genitalia (testicular evaluation is essential)
• Evaluation of the extent of virilization
• Test for levels of the following hormones:
  • Follicle-stimulating hormone (FSH)
  • Luteinizing hormone (LH)
  • Prolactin
  • Testosterone
• Thyroid function test
• Assessment of sense of smell (this is affected in individuals with Kallmann syndrome)
• Seminal fluid examination
• Imaging studies of the brain and pelvic region, as required
• Biopsy of testis, if required
• Molecular genetic testing (karyotyping)

Evaluation in females may include some of the following tools:

• Genital anomalies of development
• Medical history evaluation for acquired and congenital conditions causing Hypogonadism, particularly Turner syndrome
• Menarche - age of first occurrence of menstruation in girls; menstrual history
• Evaluation of the extent of androgenization and estrogenization
• Test for levels of the following hormones:
  • Follicle-stimulating hormone (FSH)
  • Luteinizing hormone (LH)
  • Prolactin
  • Estradiol
• Antiovarian antibody levels: If gonadotropin levels are elevated, then blood tests to rule out an autoimmune disorder may be undertaken
• Thyroid function test
• 17-hydroxyprogesterone blood test
• Imaging studies of the brain and pelvic region, as required
• Molecular genetic testing (karyotyping)

After the above initial tests, other tests may be necessary to aid in the diagnosis of the condition.

• If the brain is involved (or the pituitary gland/hypothalamus), then imaging of the brain via an MRI or CAT scan may help identify tumors/other causes for the condition
• Genetic tests to establish an underlying genetic/chromosomal disorder that may be the cause of Hypogonadism, if necessary

Other specific tests and exams may be necessary based on the underlying condition noted/diagnosed. Apart from the above, differential diagnosis to eliminate a host of conditions may be considered:

• 3-Beta-hydroxysteroid dehydrogenase deficiency
• 5-Alpha-reductase deficiency
• Adrenal hypoplasia
• Amenorrhea
• Androgen insensitivity syndrome
• Anorexia nervosa
• CHARGE syndrome
• Congenital adrenal hyperplasia
• Denys-Drash syndrome
• Disorders of sex development
• Hyperprolactinemia
• Kallmann syndrome and idiopathic hypogonadotropic hypogonadism
• Klinefelter syndrome
• Malnutrition
• Menstruation disorders in adolescents
• Pediatric adrenal insufficiency (Addison disease)
• Pediatric hypopituitarism
• Pediatric hypothyroidism
• Turner syndrome

Additional information:

• Examination of hormone levels in the blood:
  • In men, a low testosterone level may be indicative of male Hypogonadism
  • In women, low estrogen and progesterone levels may aid in the diagnosis of female Hypogonadism

Since these levels can vary based on a woman’s menstrual cycle, a more helpful way to diagnose Hypogonadism is by checking the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.

• When FSH and LH levels are low, it may indicate that the cause of Hypogonadism lies in the pituitary gland, meaning that it is not secreting stimulatory hormones for the gonads to function
• If the cause of Hypogonadism is within the gonads, then FSH and LH levels may be high, as the pituitary gland is trying to stimulate the hypo-functioning gonads

Many clinical conditions can have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Hypogonadism?

The complications of Hypogonadism may include:

• Decreased sexual function and loss of libido
• Tall stature
• Infertility - it is generally the most critical complication of Hypogonadism
• Osteoporosis is another major complication due to reduced estrogen levels, particularly in women
• Normal menstrual and reproductive function may be disrupted in females
• Testosterone therapy in men over 65 years puts them at higher risk for cardiovascular diseases and polycythemia. Also, oral testosterone can lead to liver toxicity

Complications may arise from an underlying condition/disorder/malignancy.

How is Hypogonadism Treated?

The management goals for Hypogonadism include:

• Promote and maintain sexual features and normal sexual function
• Promote and sustain normal bone development and muscle mass
• In very young children (before puberty), treatment is considered to initiate proper pubertal development
• Mental and emotional support to adolescent children with Hypogonadism

The treatment of Hypogonadism generally involves hormone replacement, which is the most important treatment in most cases. This is considered in both hypogonadotropic and hypergonadotropic Hypogonadism. However, this treatment measure does not address infertility issues. It does not also lead to gonadal growth in men and women.

• Hormonal replacement with sex steroids
  • Administration of testosterone in males: In boys and men, the administration of testosterone (for achieving puberty in boys) via injections
  • Supplementation of estrogen and progesterone in females: In women, estrogen replacement to reduce the risk for osteoporosis is usually recommended
• Oral contraceptives can help provide estrogen and progesterone in a combination that meets the replacement needs of the patient
• For improved libido in women, testosterone may be administered
• For fertility, hCG and FSH injections or administration of pulsatile LHRH therapy is considered for males with hypogonadotropic Hypogonadism
• To stimulate ovulation in women for fertility and conception, clomiphene citrate may be prescribed
• Glucocorticoid therapy can help with bone health
• Treating the cause of Hypogonadism if it is caused by an under-functioning pituitary gland or hypothalamus
• Suitably addressing the underlying infection/disorder/cause of Hypogonadism, if any present
• Surgery may be considered to treat underlying conditions as needed

Regular medical screening at periodic intervals with tests and examinations is necessary and recommended. Bone mineral density must be periodically checked, including serum testosterone levels and heart health.

How can Hypogonadism be Prevented?

The prevention of Hypogonadism is related to the underlying cause of the condition. In some cases, it may not be preventable. The following measures may be considered:

• Undertaking early and adequate treatment of any medical condition or infection, such as mumps or HIV infection
• Undertaking prompt and adequate treatment of any gonadal cancers that disrupt the function of the ovaries or testes
• Controlling obesity by bringing about suitable lifestyle and food habit changes
• If there is an associated genetic disorder, then:
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
• Avoiding the abuse of opioids and steroidal drugs
• Keeping diabetes under regular control
• Avoiding obesity through proper lifestyle changes and food control

What is the Prognosis of Hypogonadism? (Outcomes/Resolutions)

The prognosis of Hypogonadism depends on several factors, such as the underlying condition and its severity, among other factors. By replacing the deficient sex hormones, most men and women can cope with the condition, and the prognosis may be generally favorable.

• For fertility in females, pulsatile LHRH, or exogenous gonadotropin, can help with ovulation in 95% of the cases
• Primary Hypogonadism individuals cannot become fertile; although, in women, in vitro fertilization with donor ovum may help achieve pregnancy
• Men/women who have Hypogonadism due to hypothalamic or pituitary dysfunction can potentially become fertile with the administration of gonadotropins
• Undertaking early appropriate treatment of the underlying cause of Hypogonadism is known to improve the overall outcomes
• Generally, other complications affecting the body are not observed, but complications of the underlying condition (if any) may affect overall outcomes

Often, lifelong treatment is needed in the majority of cases. However, with adequate hormone replacement therapy, both men and women can have normal lives.

Additional and Relevant Useful Information for Hypogonadism:

The following DoveMed website link is a helpful resource for additional information:

https://www.dovemed.com/health-topics/focused-health-topics/hypogonadism-causes-symptoms-diagnosis-and-treatment