Authors: Rita Baron-Faust,Jill Buyon
Among the nonthyroid autoimmune endocrine disorders,
Addison’s disease
—autoimmune destruction of the adrenal glands—is the most common among women, typically occurring during the twenties and thirties. In half of those women, Addison’s occurs as an isolated disorder, and in the other half it occurs as part of a polyglandular endocrine disorder (see
pages 227
to
228
) or along with other autoimmune diseases.
The two triangular-shaped adrenal glands, which sit atop the kidneys, are actually two organs in one. The outer region, called the
adrenal cortex
, secretes steroid hormones like
cortisol
(also called
hydrocortisone
), which affects metabolism (how we use food and tap into stored energy) and suppresses inflammation in the body;
aldosterone
, which regulates the amount of salt excreted by the kidneys (helping to maintain blood pressure and blood volume); and small amounts of male hormones, or
androgens
. (The hydrocortisone produced by the adrenal glands is a naturally occurring form of the corticosteroid drugs used to dampen inflammation in autoimmune disease.)
The amount of steroid hormones secreted by the adrenal cortex is regulated by a “negative” feedback loop with the hypothalamus and the pituitary gland. In a negative feedback loop, a drop in one body chemical or hormone triggers a reaction to return levels to normal, restoring balance
(homeostasis).
On a chemical signal from the hypothalamus, the pituitary sends out
adrenocorticotropic hormone (ACTH)
, which directly stimulates the adrenal cortex. ACTH is actually produced in a 24-hour cycle, peaking around six o’clock in the morning and falling slowly during the day to hit its lowest level around
midnight. If levels of hydrocortisone get too high, it inhibits ACTH production and slows secretion of hydrocortisone. Emotional stress or injury can stimulate the release of ACTH and hydrocortisone, which the body needs to bounce back from stress.
The inner region of the adrenal gland, called the
medulla
, is linked to the sympathetic nervous system and reacts to emotional and physical stresses by secreting hormones like
epinephrine (adrenaline)
and
norepinephrine
(also called
noradrenaline
).
In Addison’s disease, autoantibodies attack the steroid-producing cells of the adrenal cortex, causing inflammation and fibrosis that prevent hormone secretion, and eventually completely destroy the cortex.
Adrenocortical autoantibodies
can target cells that produce specific hormones (autoantibodies can also block ACTH).
There’s a genetic component to Addison’s (most often in women with adrenal disease associated with autoimmune polyglandular syndrome), but less than a third of women with Addison’s have a family history of the disease. Genes associated with Addison’s (like DR3) are also linked to Graves’ disease and other autoimmune diseases.
It’s mainly a disease of reproductive-age women, but “we don’t know what precisely predisposes women to Addison’s disease,” remarks Paul W. Ladenson, MD, the John Eager Howard Professor of Endocrinology and Metabolism and director of the division of endocrinology at Johns Hopkins. “It appears that a variety of genes may be involved, some of which may be gender related, but that does not explain why adrenal insufficiency is more common in women.”
When the adrenal glands are not working properly, it can cause low blood pressure, often in the form of
postural hypotension
(or
orthostatic hypotension
), where you feel faint as blood pressure suddenly drops when you go from lying down to sitting up, or from sitting to standing. “Addison’s disease can present
with very nonspecific complaints, such as fatigue or loss of appetite, which makes it hard to recognize,” comments Dr. Ladenson. “But almost everyone with this disease has lost weight, whereas most people who have similar symptoms for other reasons have not.”
Very often a woman may have a minor illness (like stomach flu) or a physical stress, become extremely dehydrated, and have an episode of low blood pressure that lands them in an emergency room, says Dr. Ladenson. “It’s not unusual for a woman to have a history of emergency room visits before an alert physician notices a pattern and picks up on the possibility of Addison’s. Laboratory abnormalities, such as low urinary sodium, high potassium, and high calcium are clues that would prompt a good physician to look for adrenal insufficiency.”
In an acute adrenal crisis there can be fever, low blood pressure, abdominal pain, and even delirium. Chronic symptoms include loss of appetite, weight loss, fatigue, nausea, diarrhea, abdominal pain, anemia, and orthostatic hypotension. A darkening of the skin and mucous membranes may also occur. “The hardest part of making the diagnosis is to think of the possibility of Addison’s disease, because the laboratory testing for it is very straightforward,” comments Dr. Ladenson.
A number of laboratory tests will be performed to determine whether your symptoms are due to
adrenal insufficiency
. The adrenal glands produce salt-retaining hormones (
aldosterone
),
glucocorticoids (cortisol)
, and weak androgens. Your cortisol level will be measured before and after administration of synthetic ACTH, and imaging of the adrenal glands may also be done to rule out tumors.
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However, an intravenous infusion of 100 milligrams of hydrocortisone is usually given immediately when an adrenal crisis is suspected, and followed with 100 milligrams every eight hours until the crisis has passed or the diagnosis of Addison’s is confirmed.
Adrenocorticotropic hormone (ACTH)
is elevated in Addison’s. Normally, the ACTH level at midnight should be half of that in the morning (20 to 100 picograms per milliliter of blood, pg/mL).
Cortisol
is measured before an injection or intravenous infusion of synthetic ACTH,
cosyntropin (Cortrosyn)
. Then cortisol is measured 30 minutes and an hour later, explains Dr. Ladenson. Cortisol levels that fail to rise to more than 20 micrograms per deciliter of blood (mcg/dl) with administration of ACTH confirm the diagnosis of adrenal insufficiency.
Blood urea nitrogen (BUN)
, the amount of nitrogen in the blood in the form of urea, a normal waste product (a measure of kidney function), is elevated in people with low blood pressure. The normal BUN level is 7 to 18 mg/dl.
Urine testing
to measure sodium, potassium, and calcium, is often done. Sodium is decreased during episodes of low blood pressure (
hyponatremia
). High potassium or
hyperkalemia
compromises the kidneys’ ability to excrete potassium. Calcium can also be elevated (
hypercalcemia
) in Addison’s disease.
Other blood tests may also reveal high levels of
eosinophils
, a type of white blood cell associated with inflammation and allergies. Low red blood cell counts (anemia) are common in women with Addison’s.
Thyroid stimulating hormone (TSH)
may also be measured.
Adrenocortical autoantibodies in the blood can indicate adrenal gland autoimmunity, but hormone deficiency is needed to diagnose adrenal insufficiency.
The treatment of Addison’s involves replacing the glucocorticoid adrenal hormone with
prednisone
,
hydrocortisone (Hydrocortone, Cortef)
, or
cortisone acetate
, and mineral corticoid with
fludrocortisone (Florinef)
.
“We try to administer synthetic adrenal hormones in a way that approximates the natural pattern of adrenal steroid secretion. Since cortisol is highest in the early morning and lowest late at night, patients will take a larger dose of hydrocortisone or cortisone acetate in the morning and a smaller dose in the afternoon,” explains Dr. Ladenson. For example, many patients take 20 milligrams of hydrocortisone in the morning and 10 milligrams in the afternoon. Mineral corticoid therapy is given as a single dose of fludrocortisone.
“Our ability to assess adrenal replacement in the laboratory is limited, so we generally monitor patients’ clinical responses. Have symptoms like weight loss, nausea, or loss of appetite gone away? And are there symptoms of excessive replacement, such as weight gain, easy bruising, depressed mood, or muscle weakness?” says Dr. Ladenson. Fludrocortisone therapy is monitored by assessing blood pressure standing and lying down, and measuring serum potassium and plasma renin.
Women need to adjust their doses of hydrocortisone during the third trimester of pregnancy. And if they have an illness accompanied by fever, fludrocortisone may need to be decreased during the premenstrual period, since it can exacerbate fluid retention. Corticosteroids may also increase blood glucose levels. You’ll be advised to take in more salt (especially if you work out regularly and perspire) to guard against low sodium, since adequate sodium levels are needed to maintain normal blood pressure. It’s a good idea to wear a
MedicAlert
bracelet or necklace so that proper care can be given in an emergency.
Like other autoimmune diseases, Addison’s affects women during various stages of their lives.
Women with Addison’s disease often have menstrual irregularities or primary ovarian insufficiency (see
pages 231
to
233
). Low-dose oral contraceptives can be used to regulate the menstrual cycle, and hormone therapy (HT) can be used for menopausal symptoms, as there are no cross reactions with estrogen, says Dr. Ladenson. Fluid retention during the premenstrual period may worsen with fludrocortisone, so the dose may be decreased for a few days before menstruation.
In general, women don’t need to increase glucocorticoid medication during the first two trimesters. “However, labor and delivery are a physical stress, and
glucocorticoid coverage may need to be increased at the time of delivery,” says Dr. Ladenson. “We also switch women from oral medication to injectable corticosteroids.”
While drugs like prednisone are generally considered safe during pregnancy, fludrocortisone should be used cautiously; too much may cause a baby to be born with an underactive adrenal gland. Fludrocortisone and drugs like prednisone can pass into breast milk and may cause growth problems, so women with Addison’s are usually advised not to breast-feed. (Again, check the latest advice about drug use during pregnancy and breast-feeding with your doctor.)
The tiny
parathyroid
glands, nestled behind the thyroid gland, produce
parathyroid hormone
, which, along with vitamin D and calcitonin (a hormone secreted by cells in the thyroid gland), regulate the amount of calcium in the body.
In
autoimmune hypoparathyroidism
, autoantibodies attack the four pea-sized glands, destroying hormone-producing tissue. Researchers at Weill Cornell Medical Center reported in 1996 that autoantibodies against the calcium-sensing receptor of the parathyroid glands (which sense how much calcium is available to the body) are frequently observed in this disease.
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Calcium is not only needed to maintain bone mass, but is also required for muscle contractions. Having too little parathyroid hormone (PTH) leads to tingling and numbness in the hands and feet, muscle cramps, fatigue, irregular heartbeat, depression, and anxiety. It also causes a condition known as
tetany
, a heightened excitability of nerves that causes uncontrollable, painful spasms in the face, hands, and feet; spasms of the larynx; and sometimes seizures.
Hypoparathyroidism can occur in women with autoimmune hypothyroidism, or as part of type 1 autoimmune polyglandular syndrome. It’s diagnosed by measuring parathyroid hormone in the blood. (In hyperparathyroidism, too much calcium is removed from the bones and accumulates in the blood, causing excessive thirst and urine output, kidney stones, confusion, seizures, and even coma. It’s more common in women, and it is often caused by a benign parathyroid tumor.)
An underactive parathyroid is treated with oral calcium and vitamin D, sometimes in a form called
1,25-dihydroxyvitamin D (Calcitriol)
, to help absorb the calcium. “Because of the lack of parathyroid hormone, the kidney cant convert native vitamin D to its more active form as readily, and very large doses are needed, as high as 50,000 International Units, while the U.S. daily requirement is 600 units for healthy people and 800 IU in those older than 70,” comments Dr. Ladenson. “Calcitriol is very potent and easily absorbed by the body. Dosing has to be done carefully, because the toxic range is narrow. However, if you overtreat, you need only withhold a dose or two of Calcitriol, whereas toxicity caused by large doses of native vitamin D can take weeks to go away.” Calcitriol is usually taken in capsule form (it’s also available by injection).
You need a certain blood level of vitamin D to become pregnant. But the dose must be carefully regulated in pregnancy; taking too much vitamin D can cause the baby to be more sensitive to vitamin D and lead to problems with the parathyroid gland and a heart defect. Only small amounts of Calcitriol pass into breast milk; it has not been reported to cause problems in nursing babies.
An injectable version of parathyroid hormone
teriparatide (Forteo)
is approved for rebuilding bone in osteoporosis, and might have some utility in hypoparathyroidism in a more easily used form, says Dr. Ladenson.
I was absolutely shocked to find out that I was in menopause at age 32. Really shocked. We had been trying to have a baby for a couple of years, and finally went to see an infertility specialist. After he did some tests, he told me the reason I couldn’t get pregnant was premature ovarian failure. For some reason, he said, my body had destroyed the eggs in my ovaries. It was really hard to believe—I mean, I didn’t have any hot flashes, or anything like that. I thought you went through menopause because your ovaries started to shut down and that only happened when you got older. I cried for days. I know a lot of women have infertility problems. But this was like my body stole something from me . . . it really hurt to think I couldn’t have a child. But there wasn’t anything we could do about it, so right away we decided to adopt. Now I have a wonderful two-year-old daughter from China. I’m taking hormones and I feel OK otherwise. But I admit I feel different from
the other mothers I know, since they’re mostly my age and none of them is quote “menopausal” yet.C
ELIA
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