Adrenal insufficiency is the inability of the adrenal glands (Pic 1) to produce sufficient amount of hormones required for normal functioning of the human body. Primarily affected is the secretion of cortisol, the major glucocorticoid hormone involved in stress response, blood pressure and blood sugar level regulation. It may also involve insufficient secretion of mineralocorticoids, mainly aldosterone, which are involved in the regulation of water balance and ion levels, mainly natremia (blood sodium level) and kalemia (blood potassium level). 

Depending on the cause, adrenal insufficiency can be classified as primary or secondary and tertiary:

  • Primary adrenal insufficiency
    Adrenal insufficiency caused by failure of the adrenal gland itself is referred to as primary adrenal insufficiency. Congenital adrenal hyperplasia, caused by genetic defect in the enzymatic pathway of adrenal hormone production, and Addison disease (long-term insufficient function of adrenal glands) can manifest themselves as adrenal insufficiency.

    Addison disease is usually caused by autoimmune inflammation of the adrenal glands (often associated with autoimmune disorders) and less frequently by infections (e.g. tuberculosis, human immunodeficiency virus, fungal infections), metastatic carcinoma, hemorrhage and certain medications.

  • Secondary adrenal insuffiency
    Adrenal insufficiency can also be due to disease of the pituitary (Pic. 1) or the hypotalamus (Pic. 1) known as secondary and tertiary AI, respectively (in contrast to secondary AI, tertiary AI involves insufficient hormonal stimulation of the pituitary because of a hypothalamic disorder). The most common cause of secondary AI, however, results from the chronic therapeutic use of glucocorticoids which can suppress the hypothalamic-pituitary-adrenal axis (HPA, Pic. 2) and lead to insufficient cortisol production in response to stress. 

Adrenal insufficiency has often an insidious onset. In many cases, AI is only recognized when the patient presents with an acute crisis precipitated by a stressful illness or situation. Acute adrenal insufficiency should be considered in patients presenting with abdominal pain, nausea, diarrhea, hypotension (low blood pressure) and fever. Patients with acute AI usually appear dehydrated and lethargic. Physical examination of patients with AI is usually remarkable for hypotension, hyperpigmentation of the skin (increased amount of skin pigmentation) and muscle weakness.

In conditions when the body is exposed to a stressful situation, the symptoms may rapidly become worse and progress into a potentially life-threatening situation, known as Addisonian crisis (see „Complications“). In primary AI, when the hypothalamic-pituitary axis (the functional unit consisting of the hypothalamus and the pituitary gland, which regulates almost all other endocrine glands) secretes high levels of ACTH (hormone stimulating the function of adrenal glands) in response to low gluco- and mineralocorticoid levels, patients also experience hyperpigmentation (abnormal darkening) of skin and mucosal membranes, such as in gums and oral cavity surface. This is caused by simultaneous secretion of MSH (melanocyte-stimulating hormone) with the ACTH, resulting in increased pigmentation

Treatment of adrenal insufficiency involves replacing, or substituting, the hormones that the adrenal glands are not making. Cortisol is replaced orally with hydrocortisone tablets, a synthetic glucocorticoid, taken once or twice a day. If aldosterone is also deficient, it is replaced with oral doses of a mineralocorticoid called fludrocortisone.

Associated diseases

Addison‘s disease

Addison’s disease is sometimes used as a synonym for adrenal insufficiency, because it represents the condition of insufficient hormone production by the cortex of adrenal glands. Addison’s disease sensu stricto refers to acquired condition of impaired adrenal gland function. In developed world, this occurs mainly because of autoimmune inflammation which destroys the adrenals, a process known as autoimmune adrenalitis. In less-developed countries, the most frequent cause is destruction of adrenal glands by tuberculosis. Other possible causes include trauma, presence of metastatic tumours, or severe bleeding into the adrenals, known as Waterhouse-Friedrichsen syndrome. The destruction of adrenal gland tissue then results in chronic adrenal insufficiency, requiring hormone supplementation.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is a family of hereditary disorders characterized by the inability to synthesize cortisol from cholesterol in the adrenal cortex. Cortisol deficiency leads to increased ACTH (adrenocorticotropic hormone) production, which stimulates growth of the adrenal cortex (adrenal hyperplasia) and causes subsequent excess androgen production by the adrenal cortex. Symptoms depend on the severity of the enzyme deficiency and on the presence or absence of mineralocorticoid deficiency. However, a common finding in female CAH patients if a varying degree of virilization – development of male characteristics and an ambiguous appearance of external genitalia. Boys with milder forms of CAH are not affected, however they may present with enlarged genitalia and, in forms with mineralocorticoid deficiency, with adrenal (Addisonian) crisis.

Autoimmune diseases

Autoimmune adrenalitis can be an isolated disease, but it can be part of more complex inflammatory processes, such as Type 2 polyglandular syndrome. This condition can present with multiple autoimmune diseases affecting various endocrine glands in one patient, such as type 1 diabetes (affecting Langerhans islets of the pancreas), hyperthyroidism (increased function of the thyroid gland) and autoimmune thyroiditis (inflammation of the thyroid gland). Hypogonadism (decreased function of the sex glands) and premature ovarian failure can be also associated with this syndrome.

Risk factors

  • genetic factors
  • autoimmune disease
  • tuberculosis
  • long-term corticosteroid use
Complications

Addisonian crisis

Adrenal crisis, or Addisonian crisis, is a potentially life-threatening situation due to severely insufficient cortisol levels. This can arise due to previously undiagnosed and suddenly worsened adrenal insufficiency, or due to a stressful event (infection, trauma, or other form of stress) affecting someone with existing, chronic adrenal insuficiency. Symptoms include sudden, severe pain in the legs, back or abdomen, fever, convulsion, lethargy or personality changes, hyperkalemia (high blood potassium level), hyponatremia (low blood sodium level), hypoglycaemia (low blood sugar), low blood pressure, loss of consciousness, severe diarrhea and vomiting. This situation can be fatal and needs to be recognized early and treated with hydrocortisone (a glucocorticoid hormone) and fluid infusions.

Fertility may be affected in patients with adrenal insufficiency, depending on the exact cause.

Congenital adrenal hyperplasia

Fertility and the pregnancy rate are reduced in female patients, both with classic and non-classic forms of the disease, although non-classical forms are affected only mildly. Long-term anovulation and endometrial dysfunction (defective function of the inner uterine lining) are two characteristic fertility-related symptoms in women with CAH. Both of these symptoms can be attributed to the elevated androgens, mainly testosterone, in the serum. The excess of testosterone suppresses the pituitary, which then does not stimulate the ovaries to release oocytes. Furthermore, testosterone may interfere with the function of ovarian cells directly.

Another cause of subfertility is elevated progesterone (female sex hormone secreted during the second half of menstrual cycle, and continuously during pregnancy) which can be produced by conversion from the adrenal testosterone. Progesterone may then impair ovulation, and hinder implantation by altering the endometrium. Another reported effect of elevated progesterone is thickened cervical mucus, which may prevent the sperm from entering the uterus, therefore acting as contraception.

Addison’s disease

Addison’s disease is characterized by deficiency of cortisol, and sometimes also aldosterone and androgen hormonal precursors. The loss of adrenal androgens could possibly influence fertility and increase in spontaneous abortions and has been associated with Addison’s disease present in pregnancy, but the prognosis of pregnancies in patients with known Addison’s disease has usually been considered good. Concomitant diseases, such as autoimmune thyroid disease and premature ovarian insufficiency (POI; preterm cessation of ovarian function) are possible causes of reduced fertility in these patients, as well as inappropriate treatment of adrenal insufficiency and the burden of disease, with loss of energy and vitality required for wanting and planning a pregnancy and to bear children.

Stress conditions (in female patients)

Excess stress raises cortisol levels and drops progesterone levels (both potential signs of infertility). The adrenals produce progesterone before converting it into cortisol. If the adrenals are exhausted, they will rob other sources of progesterone, notably ovarian. This impacts on the reproductive cycle. Stress can cause anovulation and miscarriages. Patient suffering from AI is at increased risk of experiencing those symptoms due to stress conditions.

Male fertility

Male fertility is reduced mainly in patients suffering from AI due to CAH. In these patients, lower fertility may be attributed to two main factors. The first one is testicular dysfunction, caused by lower production of luteinizing hormone (a hormone secreted by the pituitary during the second half of the menstrual cycle).The luteinizing hormone secretion is supressed by the excessive amounts of adrenal testosterone, which in turn causes dysfunction of the Leydig cells in the testes and low testicular testosterone. This inhibits sperm production, leading to reduced sperm count, or even azoospermia of non-obstructive type (absence of sperm in the semen without an obstruction of the male genital tract). Sertoli cells (a type of cell present in the seminal epithelium of the testes) which are also important in the development of the sperm, are usually also affected, as the amount of their product, inhibin B, is usually lower in males with CAH. Sertoli cell dysfunction then contributes to testicular failure to produce sperm cells.

The second factor is the increased risk of testicular adrenal rest tumors (TART). These tumors arise from aberrant adrenal cells present in the testis that grow in number due to stimulation by ACTH. TART is a significant risk factor for both Leydig and Sertoli cell dysfunction, because it damages the testicular tissue due to its growth. Furthermore, the TART may obstruct the seminiferous tubules of the testis, which in turn may also lead to azoospermia (absence of sperm cells in the semen).

In most cases, prevention of adrenal insufficiency is not possible, as the function of the adrenal galnds is already severely impaired at the time of diagnosis. Prevention is possible, for example, in cases of autoimmune adrenalitis or autoimmune polyglandular syndrome, if they are diagnosed before the inflammation has destroyed the majority of the adrenal gland tissue. Adrenal insufficiency can be then prevented by proper immunosuppressive treatment to stop the progression of the inflammation. Similarly, destruction of the adrenal glands and subsequent AI caused by tuberculosis can be prevented by treatment with antituberculotics. 

In patients with already known AI, it is important to prevent the onset of adrenal crisis. Prevention of an AC requires early recognition, usually by the patient, of a problem necessitating stress dosing followed, when appropriate, by prompt access to medical care and hospital attendance.

The symptoms of adrenal insufficiency usually begin gradually. Characteristics of the disease are chronic, worsening fatigue, muscle weakness, loss of appetite, weight loss (Pic. 3). Significant portion of the patients also experiences nausea, vomiting, diarrhea, low blood pressure that causes dizziness or fainting when standing up, and in cases of primary Addison disease, skin changes – usually hyperpigmentation (Pic. 4). Mood changes, depression, low blood sugar (hypoglycaemia) and salt loss leading to a craving for salty foods are also common.

In patients with adrenal insufficiency, lower levels of cortisol cause increased susceptibility of the organism to stress. Therefore, certain lifestyle changes may be beneficial to reduce the amount of stress to which the organism is exposed, and to increase the well-being of AI patients.

Such lifestyle modification include:

  • Diet modifications – excluding pro-inflammatory foods, such as refined and hydrogenated vegetable fats (such as palm oil) processed foods and sources of excess sugar, and increasing the intake of healthy fats (coconut or olive oil), green leafy vegetables, fish, and high-fiber foods.
  • Increasing the amount of sleep.
  • Moderate amount of exercise with adequate time for regeneration.
  • Using supplements beneficial for adrenal function, such as omega-3 fish oil, licorice root, magnesium (Mg) vitamin B complex, vitamin C or vitamin D3.

The mainstay of treatment for adrenal insufficiency is pharmacotherapy which consists mainly of replacement of deficient hormones. 

Pharmacotherapy

Medical management of adrenal insufficiency can be divided into two parts: acute management of adrenal crisis, and chronic management.

Acute management

Treatment of adrenal crisis consists mainly of glucocorticoid administration and fluid support. The goal is to normalize patient’s hydratation, blood pressure, and to correct ion levels. Dexamethasone should be given to patients with suspected Addisonian crisis prior to any laboratory measurements. Intravenous hydrocortisone is used to treat Addisonian crisis following dexamethasone. In addition, fludrocortisone may be needed for mineralocorticoid replacement.

Chronic management

The main feature of chronic AI management is adequate daily supplementation of glucocorticoid and mineralocorticoid to mimic normal physiology. This should aim to maintain normal blood pressure, blood glucose, and fluid volume, and instill a sense of well-being in the patient.Patients on medication for minor illness (febrile illness or emesis) should be advised to double or triple their usual dose of glucocorticoid. In case of severe illness, they should inject themselves with a large dose of glucocorticoid and seek immediate medical attention.

Surgical therapy

Surgical intervention is not recommended for the management of conditions causing adrenal insufficiency (such Addison's disease).

If conservative medical treatments fail to achieve a pregnancy, the physician may suggest the patient to use the methods of assisted reproduction (ART). 

Assisted reproductive technology (ART) is the technology used to achieve pregnancy in procedures such as fertility medication, artificial insemination, in vitro fertilization (IVF) and surrogacy. It is reproductive technology used primarily for infertility treatments, and is also known as fertility treatment. It mainly belongs to the field of reproductive endocrinology and infertility, and may also include intracytoplasmic sperm injection (ICSI) and cryopreservation. Some forms of ART are also used with regard to fertile couples for genetic reasons (preimplantation genetic diagnosis). ART is also used for couples who are discordant for certain communicable diseases; for example, HIV to reduce the risk of infection when a pregnancy is desired.

IVF and ART generally start with stimulating the ovaries to increase egg production. Most fertility medications are agents that stimulate the development of follicles in the ovary. Examples are gonadotropins and gonadotropin releasing hormone. After stimulation, the physician surgically extracts one or more eggs from the ovary, and unites them with sperm in a laboratory setting, with the intent of producing one or more embryos. Fertilization takes place outside the body, and the fertilized egg is reinserted into the woman's reproductive tract, in a procedure called embryo transfer.

In women, aggressive chemotherapy or radiotherapy of the pelvic region, often lead to infertility, due to the damage of the follicles and/or oocytes that are present in the ovaries. For women who have a cancer diagnosis, egg freezing enables them to harvest and save their eggs before they are negatively impacted by chemotherapy.

In men, testis is one of the most radiosensitive tissues. The potential impact of radiotherapy on male fertility depends mainly on the total radiotherapy dose, tumor location, treatment volume, fractionation schedule, pre-treatment fertility status, and post-treatment survival of type-A spermatogonia (the stem cells of testes).The consequent measurable effects of chemotherapy or radiotherapy include compromised number of spermatozoa, their motility, morphology, and/or DNA integrity. The basic method used to preserve reproductive potential of the survivors of cancer treatment is cryopreservation of the sperm before gonadotoxic therapy. The advances in the field of assisted reproduction techniques and sperm banking allows semen storage even in men with low sperm quality. Sperm could be used for intrauterine insemination (IUI), when quality is fair by in vitro fertilization or by the Intracytoplasmic Sperm Injection (ICSI), when concentration and/or motility is low.

The ICSI procedure involves a single sperm carefully injected into the center of an egg using a microneedle. With ICSI, only one sperm per egg is needed. Without ICSI, you need between 50,000 and 100,000. 

Infertile couples may also resort to egg donation or embryo donation when the female partner cannot have genetic children because her own eggs cannot generate a viable pregnancy. 

The rate of success for IVF is correlated with a woman’s age. More than 40 percent of women under 35 succeed in giving birth following IVF, but the rate drops to a little over 10 percent in women over 40.

Find more about related issues

Sources

Adrenal crisis ―sourced from Wikipedia licensed under CC BY-SA 3.0
New directions for the treatment of adrenal insufficiency ―by Ruiz-Babot et al. licensed under CC BY 4.0
Adrenal insufficiency ―sourced from Fertilitypedia licensed under CC BY-SA 4.0
Adrenal Insufficiency in Cystic Fibrosis: A Rare Phenomenon? ―by Préville-Ratelle et al. licensed under CC BY 4.0
Addison's disease (patient information) ―sourced from Wikidoc licensed under CC BY-SA 3.0
Addison's disease ―sourced from Wikidoc licensed under CC BY-SA 3.0
Congenital adrenal hyperplasia ―sourced from Fertilitypedia licensed under CC BY-SA 4.0
Assisted reproductive technology ―sourced from Fertilitypedia licensed under CC BY-SA 4.0
The endocrine system ―by OpenStax College licensed under CC BY 3.0
Hypothalamic-pituitary axis ―by DRosenbach licensed under CC BY 3.0
Addisons hyperpigmentation ―by FlatOut licensed under CC0 1.0
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