Sandbox:Aditya

Epidemiology

Incidence

United States The prevalence of Addison disease is 40-60 cases per 1 million population.

Mortality/Morbidity

Morbidity and mortality associated with Addison disease usually are due to failure or delay in making the diagnosis or a failure to institute adequate glucocorticoid and mineralocorticoid replacement. [6] If not treated promptly, acute addisonian crisis may result in death. This may be provoked either de novo, such as by adrenal hemorrhage, or in the setting of an acute event superimposed on chronic or inadequately treated adrenocortical insufficiency. With slow-onset chronic Addison disease, significant low-level, nonspecific, but debilitating, symptomatology may occur. Even after diagnosis and treatment, the risk of death is more than 2-fold higher in patients with Addison disease. Cardiovascular, malignant, and infectious diseases are responsible for the higher mortality rate. [7] White and Arlt examined the prevalence of and risk factors for adrenal crisis in patients with Addison disease, utilizing a survey of Addison patients in the United Kingdom, Canada, Australia, and New Zealand. The authors' results indicated that approximately 8% of patients diagnosed with Addison disease require annual hospital treatment for adrenal crisis. In addition, the investigators concluded that exposure to gastric infection is the most important risk factor for adrenal crisis in the presence of Addison disease; diabetes and/or asthma [8] concomitant with Addison disease also increase the risk, according to White and Arlt. [9] A study by Chantzichristos et al indicated that in patients with type 1 or 2 diabetes, those who also have Addison disease have a higher mortality rate than do those with diabetes alone. Over a median follow-up period of 5.9 years, the mortality rate for diabetes patients with Addison disease was 28%, compared with 10% for those without Addison disease. The increase in the estimated relative overall mortality risk was 3.89 for the Addison disease patients compared with the other group. Although cardiovascular deaths accounted for the highest mortality rate in both groups, the death rate from diabetes complications, infectious diseases, and unknown causes was greater in the patients with Addison disease than in those with diabetes alone. [10]

Race

Addison disease is not associated with a racial predilection.

Sex

Idiopathic autoimmune Addison disease tends to be more common in females and children.

Age

The most common age at presentation in adults is 30-50 years, but the disease could present earlier in patients with any of the polyglandular autoimmune syndromes, congenital adrenal hyperplasia (CAH), or if onset is due to a disorder of long-chain fatty acid metabolism.

Classification

Adrenal insufficiency disorders may be classified into acute and chronic forms, depending on the timing of presentation and duration and into primary and secondary, depending on the etiology of adrenal insufficiency.

Based on the duration of symptoms

Acute adrenal insufficiency

• Adrenal crisis

Chronic adrenal insufficiency

• Chronic primary adrenal insufficiency
• Chronic secondary adrenal insufficiency

Based on etiology

Primary adrenal insufficiency(Addisons disease)

• Anatomic destruction of the adrenal gland
• Infection (TB)
• Congenital adrenal hyperplasia

Secondary adrenal insufficiency

• Hypothalamic-pituitary axis suppression

Pathology

Cortisol is normally produced by the adrenal glands, which are located just above the kidneys. It belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Scientists think that cortisol possibly has hundreds of effects in the body. Cortisol's most important job is to help the body respond to stress. Among its other vital tasks, cortisol;

Helps maintain blood pressure and cardiovascular function Helps slow the immune system's inflammatory response Helps balance the effects of insulin in breaking down sugar for energy Helps regulate the metabolism of proteins, carbohydrates, and fats Helps maintain proper arousal and sense of well-being Because cortisol is so vital to health, the amount of cortisol produced by the adrenals is precisely balanced. Like many other hormones, cortisol is regulated by the brain's hypothalamus and the pituitary gland, a bean-sized organ at the base of the brain. First, the hypothalamus sends "releasing hormones" to the pituitary gland. The pituitary responds by secreting hormones that regulate growth, thyroid function, adrenal function, and sex hormones such as estrogen and testosterone. One of the pituitary's main functions is to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals receive the pituitary's signal in the form of ACTH, they respond by producing cortisol. Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH.

Aldosterone Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. It helps maintain blood pressure and water and salt balance in the body by helping the kidney retain sodium and excrete potassium. When aldosterone production falls too low, the kidneys are not able to regulate salt and water balance, causing blood volume and blood pressure to drop.

Laboratory

Evaluating a patient with suspected adrenal insufficiency is a three-step process: establishing the diagnosis, differentiating between primary and secondary adrenal insufficiencies, and looking for the cause of adrenal insufficiency.

8 am cortisol

>15Ug/dL

3-15Ug/dL

<3Ug/dL

Adrenal insufficiency is ruled out

Measure ACTH

30 min cortisol during cosyntropin stimulation test

>18Ug/dL

<18Ug/dL

Adrenal insufficiency is ruled out

Adrenal insufficiency confirmed

Measure ACTH

Low/normal

Elevated

Secondary Adrenal insufficiency

Primary Adrenal insufficiency

Adrenal crisis=

Supportive Therapy

• IV access should be established immediately with an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension.

Mecial Management

• Preferred regimen (1): Dexamethasone sodium phosphate 4 mg iv q24h
• Preferred regimen (2): Hydrocortisone sodium succinate 50-100 mg iv q8h
• Note: Infusion may be initiated with 100 mg of hydrocortisone as an IV bolus with saline and infuse over 24 h to avoid needing to renew the infusion every 8-10 hours.

The infusion method maintains plasma cortisol levels more adequately at steady stress levels, especially in the small percentage of patients who are rapid metabolizers and who may have low plasma cortisol levels between the IV boluses. Clinical improvement, especially blood pressure response, should be evident within 4-6 hours of hydrocortisone infusion. Otherwise, the diagnosis of adrenal insufficiency would be questionable. After 2-3 days, the stress hydrocortisone dose should be reduced to 100-150 mg, infused over a 24-hour period, irrespective of the patient's clinical status. This is to avoid stress gastrointestinal bleeding. As the patient improves and as the clinical situation allows, the hydrocortisone infusion can be gradually tapered over the next 4-5 days to daily replacement doses of approximately 3 mg/h (72-75 mg over 24 h) and eventually to daily oral replacement doses, when oral intake is possible. As long as the patient is receiving 100 mg or more of hydrocortisone in 24 hours, no mineralocorticoid replacement is necessary. The mineralocorticoid activity of hydrocortisone in this dosage is sufficient. Thereafter, as the hydrocortisone dose is weaned further, mineralocorticoid replacement should be instituted in doses equivalent to the daily adrenal gland aldosterone output of 0.05-0.20 mg every 24 hours. The usual mineralocorticoid used for this purpose is 9-alpha-fludrocortisone, usually in doses of 0.05-0.10 mg per day or every other day. Patients may need to be advised to increase salt intake in hot weather.

hese drugs are used for replacement therapy in Addison disease and secondary adrenocortical insufficiency. [3, 4] Prednisone (Deltasone, Sterapred, Orasone)

View full drug information Used for glucocorticoid hormone replacement. Longer acting than hydrocortisone, with a biologic half-life of 18-36 h. Fludrocortisone (Florinef)

View full drug information Synthetic adrenocortical steroid with very potent mineralocorticoid activity. For use in Addison disease and states of aldosterone deficiency. Hydrocortisone sodium succinate or phosphate (Cortef, Hydrocortone)

View full drug information Drug of choice for steroid replacement in acute adrenal crisis and for daily maintenance in patients with Addison disease or secondary adrenocortical insufficiency. Has both glucocorticoid and mineralocorticoid properties. Biologic half-life is 8-12 h. Easiest way to set up infusion is to have pharmacy mix 100 mg of hydrocortisone in 100 mL of 0.9 saline.

Surgery

Parenteral steroid coverage should be used in times of major stress, trauma, or surgery and during any major procedure. During surgical procedures, 100 mg of hydrocortisone should be given, preferably by the IM route, prior to the start of a continuous IV infusion. The IM dose of hydrocortisone assures steroid coverage in case of problems with the IV access. When continuous IV infusion is not practical, an intermittent IV bolus injection every 6-8 hours may be used. After the procedure, the hydrocortisone may be rapidly tapered within 24-36 hours to the usual replacement doses, or as gradually as the clinical situation dictates. Mineralocorticoid replacement usually can be withheld until the patient resumes daily replacement steroids. Addison’s disease (also known as primary adrenal insufficiency or hypoadrenalism) is a rare disorder of the adrenal glands. It affects the production of two essential hormones called cortisol and aldosterone.

PCOS

Historical Perspective

PCOS was first described in 1935 by American gynecologists Irving F. Stein, Sr. and Michael L. Leventhal, from whom its original name of Stein–Leventhal syndrome is taken. The earliest published description of PCOS was in 1721 in Italy. Cyst-related changes to the ovaries were described in 1844.

• In 1721, a description symptoms resembling PCOS was published in Italy
• In 1844, Cyst-related changes to the ovaries were first described.
• In 1935, Irving F. Stein, Sr. and Michael L. Leventhal, American gynecologists, described PCOS for the first time.

Pathophysiology

• The pathophysiology of PCOS is not well understood. There are several organ systems involved in the pathogenesis of PCOS like ovary, adrenal, hypothalamus, pituitary, or insulin-sensitive tissues. It is possible that there are subsets of women with PCOS wherein each of these proposed mechanisms serves as the primary defect.
• Insulin resistance leads to compensatory insulin hypersecretion by the pancreas in order to maintain normoglycemia.
• The resulting hyperinsulinemia promotes ovarian androgen output and may also promote adrenal androgen output.
• High insulin levels also suppress hepatic production of sex hormone binding globulin (SHBG), which exacerbates hyperandrogenemia by increasing the proportion of free circulating androgens.
• Another factor that promotes ovarian androgen output is the fact that women with PCOS are exposed long term to high levels of LH.
• This LH excess seems to be a result of an increased frequency of gonadotropin releasing hormone pulses from the hypothalamus.
• The abnormal hormonal milieu also probably contributes to incomplete follicular development which results in polycystic ovarian morphology.

↑ 5α-reductase reductivity

↓ Hβ-HSD1 activity

↑ Cortisol metabolism

↑ ACTH

↑ Adrenal androgens

Normal serum cortisol

PCOS

Risk Factors

Common risk factors in the development of polycystic ovary syndrome are

• Hyperinsulinemia secondary to insulin resistance; associated with type 2 diabetes mellitus
• Obesity
• Family history of PCOS among first-degree relatives

Associated Conditions

Common conditions associated with PCOS are

• Type 2 diabetes
• Endometrial hyperplasia and cancer
• Infertility
• Hypertension
• Gestational diabetes
• Preeclampsia
• Hirsutism
• Acne

History

Obtaining the history is the most important aspect of making a diagnosis of PCOS. It provides insight into the cause, precipitating factors and associated comorbid conditions.

• Menstrual abnormalities
• Infertility
• Signs of virilization on physical examination
• Family history of PCOS among first-degree relatives

Symptoms

The most common symptoms of PCOS include

• Amenorrhea or oligomenorrhea
• Abnormal uterine bleeding
• Androgenization, including hirsutism (often slowly progressive), acne, oily skin (common)
• Polycystic ovaries, with or without ovarian enlargement
• Insulin resistance
• Endometrial hyperplasia

Laboratory Findings

Measurement of the plasma levels of several hormones is helpful in supporting the diagnosis of PCOS and especially in excluding other disorders. Determining the LH/FSH ratio of 3:1 is virtually diagnostic of PCOS; however, a normal ratio does not exclude the diagnosis, as LH levels fluctuate widely throughout the course of a day. Other androgens are measured to screen for other virilizing adrenal tumors. Fasting blood glucose is measured to look for diabetes; screening for lipid abnormalities is also employed. Testosterone is measured to exclude a virilizing tumor. Prolactin is measured to exclude a prolactinoma. Thyroid-stimulating hormone (TSH) is measured to rule out hypothyroidism

Harmone		Normal value	PCOS Laboratory Findings
LH/FSH ratio		<3;1	A ratio >3:1 is indicative of PCOS
Testosterone		Free: 100 to 200 pg/dL Total: 20 to 80 ng/dL	An elevated free testosterone level (200-400 pg/dL) is suggestive of PCOS,
Prolactin		3.8 to 23.2 μg/L	A level >300 μg/L is virtually diagnostic of prolactinoma.
TSH		0.4 to 4.2 mIU/L	Levels are normal in patients with PCOS
Androgens	Sex hormone–binding globulin	1.5 to 2.0 μg/mL	Decreased
	Androstenedione	75 to 205 ng/dL	Increased
	Estrone:	1.5 to 25.0 pg/mL	Increased
	Dehydroepiandrosterone sulfate	50 to 450 μg/dL	Increased but are <800 μg/dL
	17-Hydroxyprogesterone (follicular phase)	15 to 70 ng/dL	Normal
Fasting blood glucose		<110 mg/dL	>126mg/dL Indicates DM

Ultrasound findings

Typical ultrasound findings in patients with PCOS include

• Two- to 5-fold ovarian enlargement
• Thickened stroma (tunica albuginea)
• Thecal hyperplasia with an increase in stromal content
• Multiple (12+) subcapsular follicles ranging from 2 to 9 mm in diameter ('pearl necklace' appearance)
• Hyperplastic endometrium despite low estrogen production (due to high estrone production from the increased circulating androgens and lack of opposition by progesterone)

Epidemiology and demographics

Prevalence

• Approximately 5% to 10% of women of reproductive age are affected
• Prevalence among first-degree relatives of patients with PCOS is 25% to 50%, suggesting a strong inheritance of the syndrome; there is evidence for possible X-linked dominant transmission

Age

• PCOS can appear anytime from menarche until menopause but generally is seen around menarche and is diagnosed then or in early adulthood

Differentiating PCOS from other diseases

Disease	Differentiating Features
Pregnancy	Pregnancy always should be excluded in a patient with a history of amenorrhea Features include amenorrhea or oligomenorrhea, abnormal uterine bleeding, nausea/vomiting, cravings, weight gain (although not in the early stages and not if vomiting), polyuria, abdominal cramps and constipation, fatigue, dizziness/lightheadedness, and increased pigmentation (moles, nipples) Uterine enlargement is detectable on abdominal examination at approximately 14 weeks of gestation Ectopic pregnancy may cause oligomenorrhea, amenorrhea, or abnormal uterine bleeding with abdominal pain and sometimes subtle or absent physical symptoms and signs of pregnancy
Hypothalamic amenorrhea	Diagnosis of exclusion Seen in athletes, people on crash diets, patients with significant systemic illness, and those experiencing undue stress or anxiety Predisposing features are as follows weight loss, particularly if features of anorexia nervosa are present or the BMI is <19 kg/m2 Recent administration of depot medroxyprogesterone, which may suppress ovarian activity for 6 months to a year Use of dopamine agonists (eg, antidepressants) and major tranquilizers Hyperthyroidism In patients with weight loss related to anorexia nervosa, fine hair growth (lanugo) may occur all over the body, but it differs from hirsutism in its fineness and wide distribution
Primary amenorrhea	Causes include reproductive system abnormalities, chromosomal abnormalities, or delayed puberty If secondary sexual characteristics are present, an anatomic abnormality (eg, imperforate hymen, which is rare) should be considered If secondary sexual characteristics are absent, a chromosomal abnormality (eg, Turner syndrome ) or delayed puberty should be considered
Cushing syndrome	Cushing syndrome is due to excessive glucocorticoid secretion from the adrenal glands, either primarily or secondary to stimulation from pituitary or ectopic hormones; can also be caused by exogenous steroid use Features include hypertension, weight gain (central distribution), acne, and abdominal striae Patients have low plasma sodium levels and elevated plasma cortisol levels on dexamethasone suppression testing
Hyperprolactinemia	Mild hyperprolactinemia may occur as part of PCOS-related hormonal dysfunction Other causes include stress, lactation, and use of dopamine antagonists A prolactinoma of the pituitary gland is an uncommon cause and should be suspected if prolactin levels are very high (>200 ng/mL) Physical examination findings are usually normal As in patients with PCOS, hyperprolactinemia may be associated with mild galactorrhea and oligomenorrhea or amenorrhea; however, galactorrhea also can occur with nipple stimulation and/or stress when prolactin levels are within normal ranges A large prolactinoma may cause headaches and visual field disturbance due to pressure on the optic chiasm, classically a gradually increasing bitemporal hemianopsia
Ovarian or adrenal tumor	Benign ovarian tumors and ovarian cancer are rarely causes of excessive androgen secretion; adrenocortical tumors also can increase the production of sex hormones Abdominal swelling or mass, abdominal pain due to fluid leakage or torsion, dyspareunia, abdominal ascites, and features of metastatic disease may be present Features of androgenization include hirsutism, weight gain, oligomenorrhea or amenorrhea, acne, clitoral hypertrophy, deepening of the voice, and high serum androgen (eg, testosterone, other androgens) levels In patients with an androgen-secreting tumor, serum testosterone is not suppressed by dexamethasone
Congenital adrenal hyperplasia	Congenital adrenal hyperplasia is a rare genetic condition resulting from 21-hydroxylase deficiency The late-onset form presents at or around menarche Patients have features of androgenization and subfertility Affects approximately 1% of hirsute patients More common in Ashkenazi Jews (19%), inhabitants of the former Yugoslavia (12%), and Italians (6%) Associated with high levels of 17-hydroxyprogesterone A short adrenocorticotropic hormone stimulation test with measurement of serum17-hydroxyprogesterone confirms the diagnosis Assays of a variety of androgenic hormones help define other rare adrenal enzyme deficiencies, which present similarly to 21-hydroxylase deficiency
Anabolic steroid abuse	Anabolic steroids are synthetic hormones that imitate the actions of testosterone by increasing muscle bulk and strength Should be considered if the patient is a serious sportswoman or bodybuilder Features include virilization (including acne and hirsutism), often increased muscle bulk in male pattern, oligomenorrhea or amenorrhea, clitoromegaly, gastritis, hepatic enlargement, alopecia, and aggression Altered liver function test results are seen
Hirsutism	Hirsutism is excessive facial and body hair, usually coarse and in a male pattern of distribution Approximately 10% of women report unwanted facial hair There is often a family history and typically some Mediterranean or Middle Eastern ancestry May also result from use of certain medications, both androgens, and others including danazol, glucocorticoids, cyclosporine, and phenytoin Menstrual history is normal When the cause is genetic, the excessive hair, especially on the face (upper lip), is present throughout adulthood, and there is no virilization When secondary to medications, the excessive hair is of new onset, and other features of virilization, such as acne and deepened voice, may be present

Complications

• Endometrial hyperplasia
• Endometrial cancer
• Type 2 diabetes and its microvascular and macrovascular complications

Prognosis

• The prognosis for fertility is very good with treatment. With careful follow-up, ovarian hyperstimulation, multiple pregnancy, and endometrial hyperplasia can be avoided
• Patients should be counseled regarding the long-term risk of diabetes, hypertension, and endometrial hyperplasia, including the importance of maintaining a BMI <25 kg/m2and control of type 2 diabetes.

Surgery

Surgery is not considered first-line therapy for PCOS and it does not affect insulin resistance or obesity

Indication

Surgery is indicated in the treatment of PCOS only in patients desiring fertility in whom at least 1 year of conservative therapy has failed

Surgial options

Ovarian drilling

• Laparoscopic surgery that uses a laser or electrosurgical needle to puncture a number of small follicles visible on the surface of the ovary, which are presumably the source of hormone production

Complications

• Bleeding and/or infection
• Postoperative adhesions

Medical Therapy

The first step in the management of PCOS is weight loss if the patient is obese, and treatment of type 2 diabetes, if present, with metformin. In significantly overweight patients, weight loss alone usually effects a cure and should always be vigorously attempted. Diet and exercise are recommended in all women with PCOS. The next step is initiation of treatment to break the self-perpetuating anovulatory cycling, either by stimulating ovulation or suppressing androgenic and ovarian activity. The selection of treatment depends on whether pregnancy is desired. All antiandrogen treatments will take at least 3 months to affect hirsutism. The goals of treatment are:

• Exclude androgen-secreting tumors, endometrial tumors, and endometrial hyperplasia
• Reduce ovarian androgen secretion and/or antagonist activity at target tissues
• Interrupt the self-sustaining abnormal hormonal cycle
• Normalize the endometrium
• Restore fertility by correcting anovulation, if desired
• Reduce insulin resistance

Medical Management

If fertility is not desired

• Preferred regimen (1): Combined oral contraceptive pills one tablet of formulations containing 30 to 35 μg estrogen orally daily for 21 days, then nothing for 7 days
• Preferred regimen (2): Progesterone-only contraceptive pills (eg, norethindrone , norgestrel ) are the treatment of choice if combined oral contraceptive pills are contraindicated
• Alternative regimen(1): Medroxyprogesterone may be used, although it is not approved by the U.S. Food and Drug Administration (FDA) for this indication
• Alternative regimen(2): Glucocorticoids (eg, hydrocortisone , cortisone , dexamethasone ) may be used to suppress adrenal androgen production, although they are not approved by the FDA for this indication
• Alternative regimen(3): Spironolactone and flutamide are androgen receptor antagonists that may be added to the oral contraceptive pill, but they are not approved by the FDA for this indication; flutamide is not usually recommended because of its unproven efficacy and associated risk of hepatic impairment

If fertility is desired

• Preferred regimen (1): Clomiphene, alone or in combination with glucocorticoids, is the first-choice treatment
• Preferred regimen (2): Follicle-stimulating hormone may be administered in conjunction with timed human chorionic gonadotropin for ovulation induction
• Preferred regimen (3): Metformin

Primary Prevention

There is no established method for prevention of PCOS

Secondary Prevention

Secondary preventive measures for PCOS include

• Weight loss and metformin may prevent diabetes and atherosclerosis.
• Lifestyle modification, including increased physical activity and healthy diet resulting in weight loss, is also likely to prevent diabetes in PCOS.