Addison Disease

The adequacy of glucocorticoid replacement (hydorcortisone, prednisone) must be assessed clinically. A WBC (white blood count) with differential (the percentage of lymphocytes and polymorphonuclear (PMN) leukocytes) can help, since patients whose replacement dose is too high tend to have a relative lymphopenia (lower percent lymphocytes), while those on excessive doses tend to have a higher percent PMN leukocytes.

Patients receiving fludrocortisone (Florinef) can be assessed for adequacy of replacement by assessment of blood pressure and serum sodium (Na) and potassium (K). Sometimes these can be normal but patients may be under-replaced and not feeling completely well; assessment of plasma renin activity (PRA) may help, since it tends to be elevated in patients who are not receiving adequate fludrocortisone.

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Background: Prolactin is a peptide hormone that is produced and released from the anterior pituitary. The pituitary is an autonomous prolactin factory. The pituitary will produce increased amounts of prolactin automatically unless it is inhibited from doing so by dopamine, a hormone secreted by the adjacent hypothalamus; dopamine travels down the pituitary stalk to the pituitary gland.

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Diabetes Caused By Protease Inhibitor Therapy for HIV/AIDS

Protease inhibitors refer to a group of medications used to stop replication of the HIV (human immunodeficiency virus) retrovirus. They are very effective medications and remain an essential element in the HIV/AIDS cocktail of drugs, also known as “HAART” (Highly Active Antiretroviral Therapy). AIDS is an acronym for “acquired immunodeficiency syndrome”.

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The following discussion of hypothyroidism is intended to be understandable and practical.   I’ll first present a glossary of terms and then a description of hypothyroidism in adults: symptoms, causes, testing, and treatment.   Then I have sections on special groups with hypothyroidism: pregnant women, newborn infants, and children.  I first published this online as a Google “Knol”.


Thyroid gland refers to the endocrine organ located in the low anterior (front) of the neck. The thyroid gland secretes two forms of thyroid hormone (T4 and T3) to regulate the body’s metabolism.  The thyroid gland weighs only about 15 grams (0.5 ounces) and is shaped something like a butterfly, with wings (lobes) flanking the trachea (windpipe) and connected to each other in front of the trachea.  Figure1:

T4, thyroxine, levothyroxine (synonyms) refers to the form of thyroid hormone that has 4 atoms of iodine in each molecule.  T4 is the main hormone secreted by the thyroid gland.  Over 99% of T4 circulates in the bloodstream attached to proteins (eg, thyroid binding globulin, TBG).  The unattached T4 is known as free T4 (FT4, free thyroxine) and only that tiny portion of T4 can leave the circulating blood to enter cells.

T3, triiodothyronine (synonyms) refers to the form of thyroid hormone that has 3 atoms of iodine in each molecule.  T3 is secreted by the thyroid gland and also made from T4 in other cells that can convert T4 to T3.   Over 99% of T3 circulates in the bloodstream attached to proteins (eg, thyroid binding globulin, TBG).  The unattached T3 is known as free T3 (FT3) and only that tiny portion of T3 can leave the circulating blood to enter cells.  FT3 is active thyroid hormone and works by entering a cell’s nucleus (center) and binding to certain receptors (like a key in a lock) to regulate the activity of genes. T3 receptors are found in nearly every cell of the body, from the brain to the skin, such that thyroid hormone’s effect is extremely widespread and profound.

TSH (Thyroid Stimulating Hormone) refers to a hormone that is produced by the pituitary, a small endocrine gland that lies at the base of the brain. TSH stimulates the thyroid gland to produce T4 and T3.  The normal pituitary gland secretes more TSH when thyroid hormone levels are too low (hypothyroidism).  The TSH level is elevated when the thyroid gland fails.


Symptoms of Hypothyroidism in Adults

Most adults with hypothyroidism complain of fatigue, weight gain, and feeling cold. There are many symptoms of hypothyroidism that vary considerably among individuals and most people with hypothyroidism will have only a few of them.

Common Symptoms of Hypothyroidism: slow heart rate (bradycardia), high blood pressure, cold intolerance, fatigue, depression, mental dullness, puffiness in face or extremities, thyroid enlargement (goiter), headache, slow speech, hoarse voice, heavy menstrual periods, joint and muscle pains, tingling feeling (paresthesia), carpal tunnel syndrome, hair breakage and thinning, brittle nails, decreased perspiration and dry skin, skin pallor or yellowing, weight gain.

Uncommon Symptoms of Hypothyroidism in Adults: 

Trouble swallowing (dysphagia), breast milk secretion when not nursing (galactorrhea), shortness of breath, pneumonia, weight loss from decreased appetite, absent menstrual periods (amenorrhea), psychosis, sensitivity to narcotics and reduced consciousness. and coma.

Causes of Hypothyroidism in Adults

Hashimoto thyroiditis (autoimmune thyroiditis) is the most common cause of hypothyroidism. Dr. Hakaru Hashimoto, a Japanese surgeon, first described the condition in 1912. It’s an autoimmune condition in which the body’s immune system is turned against the thyroid.  White blood cells  (B lymphocytes) invade the thyroid gland, such that the condition is also known as chronic lymphocytic thyroiditis. The thyroid gland may enlarge and develop a rather firm, rubbery texture.  The blood contains antibodies (immune proteins) that are directed against the thyroid gland.  Such antithyroid antibodies are found in about 10% of most adult populations.  Hashimoto thyroiditis is usually a chronic condition that can eventually damage the thyroid to cause hypothyroidism.

Painless thyroiditis,also known as Hashitoxicosis, is an acute autoimmune inflammation of the thyroid gland that releases stored thyroid hormone and initially causes hyperthyroidism, followed by hypothyroidism, due to thyroid damage.  Frequently, the thyroid recovers normal function.  The condition is termed postpartum thyroiditis when it occurs in women within 6 months after delivery.

There is a very strong genetic predisposition to autoimmune thyroiditis.  Hashimoto thyroiditis can also occur during treatment with lithium, amiodarone, interferon therapy, and immuno-chemotherapy with immune checkpoint inhibitors.  Dietary iodine supplementation also appears to increase the risk of autoimmune thyroiditis.

When Hashimoto thyroiditis causes hypothyroidism, it is usually permanent.  However, up to 11% of patients with hypothyroidism may experience a remission after several years.

Rarely, hypothyroidism can resolve and may even go on to hyperthyroidism due to Graves disease.   Graves disease is an autoimmune thyroiditis in which antibodies stimulate the thyroid’s TSH receptors, causing the thyroid to produce excessive amounts of thyroid hormone.  In Graves disease, there is usually concurrent Hashimoto thyroiditis. Rarely, hypothyroidism may alternate with hyperthyroidism.

Although autoimmune thyroiditis can occur at any age and in either sex, it typically affects women.  The sexual disparity is striking, with a female: male ratio of 10:1.  Other autoimmune conditions also tend to be more common in women and the reason for this is not understood.  One debated theory is that, during pregnancy, fetal cells enter the mother and might cause an autoimmune reaction, but autoimmune disease occurs even in women who have never been pregnant.

Usually, autoimmune thyroiditis is an isolated condition.  However, individuals with autoimmune thyroiditis are somewhat prone to develop other autoimmune conditions.  Some degree of Sjoegren syndrome (dry eyes & mouth) is fairly common.  Celiac disease, an autoimmunity against the intestine provoked by gluten (wheat), is also more common.  Vitiligo (patches of white skin) can also occur.  In polyglandular autoimmune syndromes, patients with autoimmune thyroiditis have other autoimmune endocrine deficiencies, such as adrenal insufficiency, hypoparathyroidism (low serum calcium), or type 1 diabetes mellitus,

Other causes of hypothyroidism include surgery, radioiodine treatment or exposure (nuclear fallout), chronic hepatitis C, Reidel thyroiditis, and certain drugs: lithium, propylthiouracil, methimazole, sulfonamides, amiodarone, interferon alpha, interferon beta, interleukin-2.  Iodine deficiency can cause hypothyroidism and goiter. Certain foods (turnips, cassava) can aggravate iodine deficiency and are known as goitrogens.  Hypopituitarism can cause hypothyroidism, due to a deficiency of TSH.

Tests for Hypothyroidism

When the thyroid gland fail, lower levels of thyroid hormone are sensed by the pituitary gland, which secretes more Thyroid Stimulating Hormone (TSH). An elevated serum TSH level is the most sensitive test for hypothyroidism (except with hypopituitarism)  In hypothyroidism, the serum free T4 (FT4) level is usually low or low-normal.

To screen for Hashimoto (autoimmune) thyroiditis, blood is assayed for antithyroid antibodies: anti-thyroperoxidase (TPO) antibodies and anti-thyroglobulin (TG) antibodies.


Factors that can cause misleading testing for hypothyroidism:

When a serum TSH level is elevated, the test should be repeated before embarking on long-term thyroid hormone replacement.  Certain factors can cause a misleadingly elevated serum TSH that may be mistaken for hypothyroidism: recovery from an illness, acute psychiatric crises, sleep deprivation, and strenuous exercise just before testing. Heroin or amphetamines can also elevate serum TSH.  Misleadingly elevated serum TSH levels may also be caused by spurious test results resulting from laboratory error or from circulating antibodies that interfere with the TSH antibody assay method or block the TSH receptor.

Misleadingly low serum total T4 levels occur with malnourishment and factors that reduce serum protein levels, such as cirrhosis and nephrotic syndrome. Other conditions that can lower TBG and result in a misleadingly low serum total T4 include anabolic steroid abuse and familial TBG deficiency.  Serum free T4 (FT4) levels are normal in these conditions and the FT4 assay is superior to the total T4 assay.

However, misleadingly low serum FT4 levels can also occur and can result from laboratory error or can be seen in severe illness, particularly congestive heart failure.  Certain drugs also cause low FT4 levels without hypothyroidism: high-dose corticosteroids (eg, prednisone, dexamethasone), anti-seizure drugs (eg, carbamazepine, phenytoin, phenobarbitol), and therapy with T3 (Cytomel).  In these conditions, the serum TSH is not elevated.

 Other Laboratory Findings in Hypothyroidism:

Certain other laboratory tests can also be abnormal in patients with hypothyroidism: hyponatremia (low serum sodium), elevated liver enzymes, elevated serum prolactin levels, and anemia.  High serum lipids are commonly sen: high LDL cholesterol, high triglycerides, and high lipoprotein(a).  In patients with autoimmune thyroiditis, serum ANA levels are usually elevated and are nonspecific, i.e., not usually indicating systemic lupus erythematosis.


Treatment of Adults with Hypothyroidism 

History:  Treatment for hypothyroidism first became available in 1892, when sheep’s thyroid was fried and eaten to treat this condition.  This was not particularly palatable.  In 1900, a thyroid preparation was first introduced in the United States as dessicated (dried) sheep’s thyroid that had been freed from fat, cleaned, dried, and powdered.  It could be made into tablets whose dosage was measured as weight in an old measurement called grains, where 1 grain (not to me confused with the word gram) is equivalent to 60 milligrams (mg).  However, the original desiccated thyroid preparations differed in potency from batch to batch, although it has become more reliable and continues to be available.  Synthetic thyroxine was developed to be a more reliable thyroid medication and that is the type of thyroid preparation in greatest use today.

Synthetic thyroxine (T4) is thyroid medication that is preferred by most clinicians for treating patients with hypothyroidism.  There are several thyroxine formulations and many dosage strengths.  Most formulations have accurate amounts of thyroxine in their tablets.  However, the bioavalability (absorption) of the different manufacturer’s thyroxine formulations can differ slightly. Therefore, it’s best for hypothyroid patients to be consistent and to take the same brand name of thyroxine or the same manufacturer’s generic thyroxine.

Beginning therapy with thyroxine:  There is no mandatory starting dosage of thyroxine.  Generally, for pregnant women, or patients with severe hypothyroidism, a full replacement dosage of thyroxine is given immediately.  For children and otherwise healthy younger adults, near-replacement doses are begun from the outset.  However, for older patients with suspected coronary disease, the replacement dosage should be lower and increased as tolerated.  If angina occurs, the dosage is reduced until coronary intervention can restore coronary artery perfusion.

Monitoring Treatment of Hypothyroidism:

Serum TSH (thyroid stimulating hormone) levels are used to monitor the adequacy of thyroxine replacement. While receiving optimal thyroxine replacement therapy, most people’s symptoms of hypothyroidism resolve fully.  Serum TSH levels are generally kept between 0.4 – 2.0 mcg/dL.  Although serum TSH levels are very useful to determine the optimal replacement dosage of thyroxine, it is important not to rely entirely on this test.

Some hypothyroid individuals who receive thyroxine replacement continue to have symptoms typical of hypothyroidism (particularly fatigue), despite having serum levels of TSH and FT4 that are solidly normal.  In such cases, it is important to screen for other conditions, such as concurrent illness (eg, anemia, diabetes, hypercalcemia, electrolyte abnormalities, celiac disease, adrenal insufficiency, hypogonadism, depression). Medications can cause fatigue (eg, oral statin drugs for treatment of high cholesterol, oral beta blockers, beta blocker eye drops for glaucoma, etc).  In the absence of such conditions, a serum T3 or FT3 can be checked.  If the serum T3 or FT3 level is low or low-normal and there are no contraindications (eg, angina, atrial fibrillation), a careful increase in thyroxine replacement is reasonable and may be continued if symptomatic relief is obtained.  But if thyroxine is given such that serum TSH levels are suppressed, the serum T3 or FT3  levels should be monitored, keeping them in the lower half of the normal reference range. Careful clinical monitoring is also required for symptoms or signs of hyperthyroidism. Periodic bone mineral densitometry may be followed, thyroid hormone replacement does not cause osteoporosis as long as they are clinically euthyroid (no signs of excess thyroid).  Individuals receiving doses of thyroxine that suppress serum TSH below 0.1 mIU/L, as a group, have been found to be at an increased risk for clinical hyperthyroidism (eg, atrial fibrillation), particularly with menopause or withdrawal of oral estrogen therapy.

Since the normal thyroid secretes both T4 and T3, there have been studies comparing T4 to combined T4/T3 thyroid preparations, which have yielded conflicting results.  Such combined T4/T3 preparations include Armour Thyroid (desiccated animal thyroid), Nature-Throid, and Liotrix (synthetic, unavailable in USA).  The main problem with giving combined T4/T3 preparations is that the T3 component peaks a few hours after taking the pill, with transiently elevated serum T3 levels.  Nevertheless, some patients subjectively prefer the T4/T3 preparations.  A Dutch double-blind study of 141 hypothyroid individuals found that their patients often preferred the T4/T3 preparation, and during such treatment, the serum TSH levels were often suppressed.

Medications that Interact with Thyroid Hormone Therapy:

Certain medications can interact with thyroid hormone replacement treatment for hypothyroidism. Care must be taken when thyroid hormone is taken with the following medications:

Amiodarone: inhibits conversion of T4 to T3; rely on serum TSH levels.

Antacids (aluminum or calcium): reduces thyroxine intestinal absorption.

Anti-tuberculous antibiotics: increase liver break-down of thyroxine.

Rifabutin (Mycobutin)

Rifampin (Rifadin, Rimactane)

Anti-sex hormone chemotherapy for breast cancer or prostate cancer:  reduces estrogen and liver TBG production, reducing thyroxine dosage requirement:

Leuprolide (Lupron, Lupron Depot): reduces estrogen and liver TBG production, reducing thyroxine dosage requirement:

Anti-seizure medications: increase liver break-down of thyroxine

Carbamazepine (Tegretol)


Primidone (Mysoline)

Phenytoin (Dilantin)

Chemotherapy: may cause ovarian failure, reducing estrogen levels and liver TBG production, reducing thyroxine dosage requirement.

Cholesterol-lowering bile acid-binding drugs: reduces thyroxine absorption

Cholestyramine (Questran)

Colestipol (Colestid)

Didanosine (ddi, Videx anti-HIV therapy): reduces thyroxine absorption

Digoxin (Lanoxin): thyroxine increases thyroxine clearance.

Estrogens (oral): increases liver production of Thyroid Binding Globulin

Oral contraceptives and oral estrogen replacement therapy:  increase in hepatic production of thyroid binding globulin (TGB) may increase thyroxine dose requirement.

Imatinib chemotherapy (Gleevec): increases liver metabolism of thyroxine

Iron supplements: reduce thyroxine absorption

Proton Pump Inhibitors (PPIs): may cause atrophic gastritis and reduce the absorption of thyroxine (omeprazole, lansoprazole, pantoprazole, etc)

Raloxifene (Evista): reduces thyroxine absorption

Sucralfate (Carafate): reduces thyroxine absorption

Warfarin (Coumadin): dosage requirement may change (usually drops), due to changes in hepatic metabolism and  clotting factors caused by thyroxine therapy.


Pregnant Women with Hypothyroidism:

Hypothyroidism is a very common condition and unsuspected maternal hypothyroidism appears to cause a 3.8% increase in miscarriage rate.

During pregnancy, the developing baby receives the mother’s thyroid hormones, which cross the placenta.  The baby is particularly dependent upon maternal thyroid during the first trimester when the fetal thyroid has not fully developed.  Maternal hypothyroidism can adversely affect the intellectual development of the baby.

Therefore, screening for hypothyroidism is reasonable for all women who are planning to become pregnant or who have become pregnant. Screening is mandatory for women with symptoms of hypothyroidism (see above) or who have a personal or family history of thyroid or autoimmune disorders.  Screening for hypothyroidism is done with a blood test for TSH.

Iodine deficiency is surprisingly common and can cause hypothyroidism during pregnancy.  This can be prevented by ensuring adequate dietary iodine with iodized salt and tea or by taking one prenatal multivitamin daily.  The multivitamin should contain 150 mcg iodine, the recommended daily requirement during pregnancy.  Excessive iodine supplements should be avoided, as this can cause the baby to develop a goiter.

Women with known hypothyroidism should have prenatal thyroid function testing to ensure they are euthyroid (normal thyroid levels) before becoming pregnant.  During pregnancy women’s thyroxine requirements predictably increase by as much as 50%.  Therefore, at the diagnosis of pregnancy the dosage of thyroxine is increased empirically by 20-30%.  It is prudent to monitor TSH levels every 6 weeks and adjust the thyroxine replacement to ensure that they are doing well clinically and to keep the TSH level below 2.0 mIU/L Following delivery, the thyroxine dosage may be tapered back gradually over several weeks to the prenatal dosage.


Newborns with Hypothyroidism:

About 1 in 3000 newborn infants are born with hypothyroidism, which is known as congenital hypothyroidism.  Hypothyroid infants may appear lethargic and have a hoarse cry. They may nurse poorly and have abdominal bloating, constipation, and vomiting.  They may also have hypothermia, a large posterior fontanelle and neonatal jaundice that persists for more than 3 days. They may develop a large tongue and a bulging around the belly button (omphalocele). However, hypothyroidism is often not clinically recognized at birth, so a mandated screening process tests all newborns for congenital hypothyroidism, usually with blood obtained from a heel stick and absorbed onto filter paper.  The blood specimen is sent to a central laboratory to assess for inborn errors of metabolism and for TSH and/or T4.  TSH levels fluctuate a great deal during the first few days of life, so there may be false positive and false negative results.

Transiently low T4 levels (with normal TSH) are commonly seen in babies who are not hypothyroid, but who are premature, low birth weight, or who are sick from other causes.  Such babies’ low T4 levels usually rise into the normal range after their recovery and there are no adverse sequelae.  However, repeat testing is advisable, since permanently low FT4 with low or normal TSH levels can be seen with congenital hypopituitarism, which is rare but must be suspected in babies with an abnormally slow growth.

Low neonatal T4 with a high TSH usually indicates hypothyroidism.  About 10% of such babies have temporary hypothyroidism; when this is suspected, at age 3-4 years, thyroxine replacement may be held for 3-4 weeks and the FT4 and TSH repeated to see if they are now normal.

Most babies with hypothyroidism have a permanent condition.  The causes of this include an absent thyroid (thyroid aplasia), an underdeveloped thyroid (thyroid hypoplasia), or an abnormally located (ectopic) thyroid under the tongue (lingual thyroid) or on the side of the neck.  Congenital hypothyroidism can also be caused by thyroid enzyme defects.

When screening tests (T4 and TSH) indicate hypothyroidism, confirmatory blood tests are drawn immediately and the baby is treated with thyroxine while the test results are pending.  Frequent monitoring of the FT4 and TSH levels is important and the FT4 level should be kept in the upper range of normal.  Thyroxine may be not be properly absorbed by the intestines of babies who receive concurrent soy formula or iron preparations.

When babies are diagnosed with hypothyroidism by newborn thyroid screening testing and treated with thyroxine, their growth and intellectual development will be entirely normal. However, when congenital hypothyroidism is untreated, the baby’s brain gradually suffers irreversible damage that results in a condition known as cretinism.


Children with Hypothyroidism:

Children who develop hypothyroidism typically have a diminished growth velocity and become shorter relative to peers of their age.  The eruption of adult teeth may be delayed.  Hypothyroid children may be somewhat overweight but often do not look particularly sick or have physical complaints. When hypothyroidism develops after age 2 years, permanent mental deficiency does not typically occur.  In fact, hypothyroid children may sometimes be good students because they lack some of the normal hyperactivity of childhood and pay attention in class. However, with more severe hypothyroidism, children can develop problems with cognitive and attention deficits that may seem like a new learning disability.  They may complain of feeling fatigued and cold and may appear depressed and lethargic.   Their skin may be dry and they may be constipated.  Girls may develop the onset of menstrual periods before age 10 years (precocious puberty) and may have heavy, painful, and irregular periods.  These symptoms reverse with treatment of their hypothyroidism.

Thyroxine replacement therapy is given to children with hypothyoidism.  Because of their increased metabolic rate, children and adolescents with hypothyroidism often require a higher relative doses (mcg/kg body weight) of thyroxine than do adults.  Autonomous adolescents may neglect to take their thyroxine medication regularly and some supervision may be required.


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Graves Disease Symptoms & Treatment

Graves disease is the most common cause of hyperthyroidism in the United States. Other causes of hyperthyroidism include multinodular goiter, toxic solitary nodules of the thyroid, and functioning thyroid cancer. Rare causes for hyperthyroidism include TSH-secreting pituitary tumors, struma ovarii, and hCG-secreting trophoblastic tumors of the ovary or testis. All of the latter conditions cause increased thyroid radioactive iodine uptake on scanning. Hyperthyroidism without increased thyroid radioiodine uptake can be caused by subacute thyroiditis, an acute phase of Hashimoto thyroiditis,  thyroid hormone intake, and iodide-induced hyperthyroidism (due to kelp, amiodarone, x-ray contrast, or potassium iodide).

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Menopause & Hormone Replacement Therapy


Attitudes towards post-menopausal HRT continue to change.  Oral HRT enjoyed widespread use through the 1990s, when it was thought to reduce cardiovascular disease.  Then came the Women’s Health Initiative (WHI), a prospective study of HRT that eventually enrolled 160,000 women.  In 2002, the WHI stopped the combined oral HRT arm of the study (daily oral conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg), finding of an increased risk of breast cancer, coronary heart disease, pulmonary embolism, and stroke.  In 2004, the WHI stopped the oral estrogen-only HRT arm of the study (daily oral conjugated equine estrogen 0.625 mg), finding a reduced risk of breast cancer but an increased risk of stroke.  With such risks of oral HRT established, the use of postmenopausal estrogen replacement dropped dramatically.  But things have changed.

Since the WHI, there has been a monumental advance in HRT; namely, transdermal estradiol preparations have been developed that do not increase the risk of coronary heart disease, pulmonary embolism, or stroke; in fact, use of transdermal estradiol in the first 15 years after menopause reduces the risk of cardiovascular disease and improves overall survival.  Transdermal estradiol can also dramatically improve many other symptoms that are described below. Additionally, breast cancer risk is not increased with low-dose estrogen replacement, using a progestin just intermittently or not at all.  The decision about using HRT must be individualized.  Each woman and her health care provider should be well-informed about HRT’s potential benefits vs risks and the variety of preparations available.

In this section, I will discuss Menopause & HRT:  1) Menopausal Symptoms; 2) Menopause Laboratory Diagnosis;  3) HRT Benefits vs Risks;  4) HRT Medications (comprehensive list);  5) Menopause: references from peer-reviewed journals (searchable). This information in also found in my chapter entitled  “Endocrine Disorders”in the medical textbook Current Medical Diagnosis & Treatment, published internationally by McGraw Hill.

Menopause – Symptoms and Signs:

  • Vasomotor symptoms (hot flushes) are experienced by 60-80% of women at menopause. Hot flushes can begin during the climacteric, years before menstrual periods cease; they can continue for decades after the menopause transition. The duration of hot flushes can vary from seconds to many minutes.  Women experience heat, particularly around the upper body, including the head, neck, chest, and back.  The severity can vary from mild to debilitating and many women experience drenching nocturnal sweats. Hot flushes peak in early menopause and then usually decline gradually over a median of 10 years, but some women continue to experience uncomfortable hot flushes after age 65. African-American women tend to experience more severe hot flushes. Asian women are less affected.   Obese women tend to have more severe hot flushes than do women at ideal body weight.  Lower socio-economic status also predisposes women to more severe hot flushes, for unknown reasons.   Smokers tend to experience worse symptoms.
  • Mild cognitive impairment commonly occurs at menopause.
  • Depression & irritability are common during menopause.  The relationship between menopause and emotional lability is often not recognized, such that many women are prescribed antidepressants when the real problem is estrogen deficiency.
  • Sleep disturbances are very common and lack of sleep may cause daytime fatigue and predispose to the cognitive impairment noted above.
  • Fatigue is common during menopause, and may be aggravated by sleep disturbances noted above.
  • Joint pains (arthralgias) are sometimes so severe in menopause that some women often seek help from rheumatologists who usually prescribe NSAIDS and may not recognize that the arthralgias are caused by estrogen deficiency.
  • Diminished libido is commonly experienced at menopause.
  • Headaches may become more frequent after menopause.
  • Postmenopausal osteoporosis with fractures is caused in large part by estradiol deficiency.
  • The skin becomes more wrinkled. 
  • Atherosclerosis risk is increased. Estradiol deficiency typically increases LDL (bad) cholesterol and reduces HDL (good) cholesterol.
  • Vulvovaginal atrophy is common after menopause, with symptoms of vaginal dryness, painful intercourse, and irritation.

A careful pelvic examination is useful to check for uterine or adnexal enlargement and to obtain a Papanicolaou smear and a vaginal smear for assessment of estrogen effect.  Vulvovaginal complaints are not always due to estrogen deficiency and direct inspection of the vulva is necessary to detect other conditions, such as lichen sclerosis, contact dermatitis, squamous hyperplasia, or malignancy.

Menopause – Laboratory Findings:

Early Menopause (< age 45): Elevated serum or urine hCG overwhelmingly indicates pregnancy.  Further laboratory evaluation for women who are not pregnant includes serum estradiol PRL, FSH, LH, and TSH. Hyperprolactinemia or hypopituitarism (without obvious cause) should prompt an MRI study of the pituitary and hypothalamus. Routine testing of kidney and liver function (BUN, serum creatinine, bilirubin, alkaline phosphatase, and alanine aminotransferase) is also performed. A serum testosterone level is obtained in hirsute or virilized women. Patients with manifestations of hypercortisolism (Cushing syndrome) receive a 1-mg overnight dexamethasone suppression test for initial screening.  Nonpregnant women without any laboratory abnormality may receive a 10-day course of a progestin; absence of withdrawal menses typically indicates a lack of estrogen or a uterine abnormality.

Normal Menopause:  No laboratory testing is required to diagnose menopause, when amenorrhea occurs at the expected age. The expected age of menopause correlates with a woman’s mother’s age at menopause and varies among different kindreds and ethnic groups. An elevated serum FSH with a low or low-normal serum estradiol helps confirm the diagnosis.


Menopause Treatment:

Nonhormonal Medical Therapy

Hot flushes may be reduced with low room temperatures, dressing coolly, and consuming cold beverages. Night sweats may be reduced by sleeping in a cool room and by avoiding the use of excessively warm blankets or down comforters. Slow, deep breathing can ameliorate hot flushes. Women may try avoiding known triggers for hot flushes, such as smoking, alcohol, caffeine, and hot spicy foods. Idiosyncratic triggers for hot flushes may be discerned and avoided. Aerobic training for 50 minutes four times weekly reduced all menopausal symptoms except vaginal dryness in a randomized controlled trial. Clinical hypnosis reduced hot flushes over 12 weeks in one study. Acupuncture may help alleviate symptoms in some women.

For women with severe hot flushes who cannot take estrogen, SSRIs may offer modest relief effective within a week; escitalopram (10-20 mg/day) can reduce hot flushes significantly, but must not be used by women taking tamoxifen for breast cancer, since it inhibits tamoxifen’s metabolism to its active metabolite. Venlafaxine extended release (75 mg/day) may also be effective and does not have a drug interaction with tamoxifen. Sexual dysfunction has not been less of a problem with the latter drugs when used for vasomotor symptoms, compared to their use for depression. Gabapentin is also quite effective in oral doses titrated up to 200-800 mg every 8 hours. Side effects such as drowsiness, fatigue, dizziness, and headache, which are most pronounced during the first 2 weeks of therapy, often improve within 4 weeks. An herb, black cohosh, may possibly relieve hot flushes. Replens is a vaginal lubricant that can be used daily or 2 hours prior to intercourse. It improves vaginal moisture and elasticity and reduces vaginal irritation and dyspareunia.


Hormone Replacement Therapy (HRT)

Estrogen replacement is most commonly prescribed for women in early menopause, when symptoms are worst and the benefits are greatest. Transdermal estrogen is favored over oral therapy to reduce the risk of thromboembolism. In women with an intact uterus, estrogen replacement without a progestin risks endometrial hypertrophy and dysfunctional uterine bleeding. The addition of an oral progestin, however, increases the risk of breast cancer. Therefore, only the smallest effective dose of estrogen should be used in order to reduce the need for progestins in such women. Progestin can be delivered directly to the uterus with progesterone-eluting intrauterine devices (Mirena IUD). The decision to take menopausal hormonal therapy and its type and duration are dictated by individual symptoms, risk profile, and personal preferences, while considering potential benefits and risks.

A. Benefits of Hormone Replacement Therapy (HRT)

  • Overall survival is improved among women who begin HRT before age 60 or within 10 years of menopause.  Women aged 50-59 years in the WHI who received estrogen alone developed significantly lower CT coronary calcium scores (a marker for coronary atherosclerosis) than women receiving placebo. In the California Teachers Study, HRT in women under age 60 was associated with a dramatic 46% reduction in all-cause mortality, particularly cardiovascular disease.  Another 20-year study of 8801 women living in a retirement community found that estrogen use was associated with improved survival. Age-adjusted mortality rates were 56.4 (per 1000 person-years) among nonusers and 50.4 among women who had used estrogen for 15 years or longer.  Although the association of HRT and lower mortality may suffer from self-selection bias, there appears to be a survival advantage of HRT that requires longer-term administration (more than 5 years) to become apparent. The survival advantage is particularly strong for women under age 60 and diminishes with age; no reduction in mortality was noted in the group of women aged 85-94 years. The reduction in cardiovascular disease among younger postmenopausal women taking HRT may be explained by the reduction in serum levels of atherogenic lipoprotein(a) with HRT, with or without a progestin. Improvement in serum HDL cholesterol is greatest with unopposed estrogen but is also seen with the addition of a progestin.  However, no survival advantage was found in much older women, according to a meta-analysis of 43 randomized controlled trials.
  • Breast cancer risk is reduced in women taking replacement estrogen alone, according to the Women’s Health Initiative Study.  However, breast cancer risk is increased among women taking combined daily estrogen and progestin (see below).
  • Hot flushes and sweats are reduced by more than 70% by HRT, usually within a month. Vaginal moisture is improved and libido is enhanced in some women.
  • Sleep disturbances are common in menopause and can be reversed with HRT.
  • Overactive bladder and vaginal dryness can be improved by HRT and by estradiol vaginal rings.
  • Mild memory impairment is often improved with HRT.  Although HRT does not prevent Alzheimer disease, short-term transdermal estradiol has been demonstrated to slightly improve memory in women with existent mild to moderate Alzheimer disease.
  • Joint pains (arthralgias), generalized body pain, and reduced physical function may be caused or aggravated by estrogen deficiency.  Some women have evaluations for arthritis by rheumatologists.  HRT often improve such symptoms.
  • Perimenopausal depression can be significantly improved with estrogen replacement.  Many women feel an overall improved sense of well-being when taking HRT.
  • Skin dryness, atrophy, seborrhea may be improved with estrogen replacement.  However, HRT does not prevent facial skin wrinkling.
  • Postmenopausal osteoporosis is prevented by HRT. The WHI study found that women who received estrogen therapy experienced a reduced number of hip fractures (six fewer fractures/year per 10,000 women) compared with placebo. Even microdose transdermal estradiol (0.014 mg/day) helps preserve bone density.


Estrogen replacement without progestin (unopposed HRT)  Interestingly and counterintuitively, the WHI study found that postmenopausal women taking unopposed estrogen had a 23% reduction in breast cancer risk. Unopposed estrogen replacement improves glycemic control in women with type 2 diabetes mellitus. Perimenopause-related depression is improved by unopposed estrogen replacement; the addition of a progestin may negate this effect.

B. Hormone Replacement Therapy (HRT): Risks

  • Breast cancer risk is slightly increased among women taking combined daily estrogen and progestin HRT, whereas breast cancer risk is slightly reduced in women taking estrogen alone.
  • Oral estrogen increases the risk of arterial and venous thrombotic events in a dose-dependent manner, although the absolute risk is small. The WHI study found that women who received long-term conventional oral combined HRT had an increased risk of deep venous thrombosis (3.5 per 1000 person-years) compared with women receiving placebo (1.7 per 1000 person-years); however, transdermal estradiol does not increase vascular thrombosis.  Oral estrogen also increases the risk of ischemic stroke by about 30%. Oral estrogen causes a particularly increased risk for thromboembolic disease among older women and those with increased stroke proclivity (current smokers and those with hypertension, atrial fibrillation, prior thromboembolic event). Long-term use of oral conjugated estrogens in women over age 65 has been associated with poorer cognitive performance, perhaps due to small strokes. Transdermal or vaginal estrogen administration avoids this risk.
  • Urinary stress incontinence appears to be increased by conventional-dose oral estrogen replacement, whereas topical vaginal estrogen may have a beneficial effect.
  • Mastalgia (breast discomfort) may occur with estrogen replacement, but typically responds to dose reduction.
  • The risk of seizures in women with epilepsy may be increased with estrogen replacement.
  • Large pituitary prolactinoma tumors may grow in response to estrogen.  However, estrogen may be taken safely by women with pituitary prolactinomas that are controlled with cabergoline.
  • Gastroesophageal reflux disease (GERD) may be increased by oral estrogen and selective estrogen receptor modulators (SERMs).
  • Hepatic hemangiomas can grow in response to oral estrogen, but significant enlargement is uncommon. Transdermal estradiol at low doses minimizes this risk.


The risks for HRT also depend on whether estrogen is administered alone (unopposed HRT) or with a progestin (combined HRT).

Estrogen replacement without progestin (unopposed HRT)  Surprisingly, the WHI study found that postmenopausal women who received conventional-dose estrogen-only therapy had a reduced risk of breast cancer (7 fewer cases/year per 10,000 women) compared with a placebo group. However, the California Teachers Study monitored women for a longer period; a group of 37,000 women who had been taking conventional-dose estrogen-only therapy for 20 years or longer did have a slightly increased risk of breast cancer. Women taking lower-dose unopposed estrogen therapy would be expected to have lower long-term risk of breast cancer.

Conventional-dose unopposed conjugated estrogen replacement (0.625 or 1.25 mg daily) increases the risk of endometrial hyperplasia and dysfunctional uterine bleeding, which often prompts patients to stop the estrogen. However, lower-dose unopposed estrogen confers a much lower risk of dysfunctional uterine bleeding. Recurrent dysfunctional bleeding necessitates a pelvic examination and possibly an endometrial biopsy. There has been considerable concern that unopposed estrogen replacement might increase the risk for endometrial carcinoma. However, a Cochrane Database Review found no increased risk of endometrial carcinoma in a review of 30 randomized controlled trials. Therefore, lower-dose unopposed estrogen replacement does not appear to confer any significant increased risk for endometrial cancer.

Long-term conventional-dose unopposed estrogen increases the mortality risk from ovarian cancer, although the absolute risk is small. The annual age-adjusted ovarian cancer death rates for women taking estrogen replacement for 10 years or longer are 64:100,000 for current users, 38:100,000 for former users, and 26:100,000 for women who had never taken estrogen. Lower-dose estrogen replacement is believed to confer a negligible increased risk for ovarian cancer.

The WHI trial was stopped in 2002 because of an increased risk of stroke among women taking conjugated oral estrogens in doses of 0.625 mg daily; the risk was about 44 strokes per 10,000 person-years versus about 32 per 10,000 person-years in women taking placebo. However, transdermal or transvaginal estrogen does not increase the risk of stroke.

Oral estrogens can cause hypertriglyceridemia, particularly in women with preexistent hyperlipidemia, rarely resulting in pancreatitis. Postmenopausal estrogen therapy also slightly increases the risk of gallstones and cholecystitis. These side effects may be reduced or avoided by using transdermal or vaginal estrogen replacement.

Estrogen replacement with a progestin (combined HRT)  Long-term conventional-dose oral combined HRT increases breast density and the risk for abnormal mammograms (9.4% versus 5.4% for placebo). There is also a higher risk of breast cancer (8 cases per 10,000 women/year versus 6.5 cases per 10,000 women/year for placebo); the increased risk of breast cancer is highest shortly after menopause (about 2 cases per 1000 women annually). This increased risk for breast cancer appears to mostly affect relatively thin women with a BMI less than 24.4. The Iowa Women’s Health Study reported an increase in breast cancer with HRT only in women consuming more than 1 oz of alcohol weekly. No accelerated risk of breast cancer has been seen in users of HRT who have benign breast disease or a family history of breast cancer. Women in whom new-onset breast tenderness develops with combined HRT have an increased risk of breast cancer, compared with women without breast tenderness.

The Women’s Health Initiative Mental Study (WHIMS) followed the effect of combined conventional-dose oral HRT on cognitive function in women 65 – 79 years old.  HRT did not protect these older women from cognitive decline. In fact, they experienced an increased risk for severe dementia at a rate of 23 more cases/year for every 10,000 women over age 65 years. It is unknown whether this finding applies to younger postmenopausal women.

In the WHI study, women receiving conventional-dose combined oral HRT experienced an increased risk of stroke (31 strokes per 10,000 women/year versus 26 strokes per 10,000 women/year for placebo). Stroke risk was also increased by hypertension, diabetes, and smoking.

Women taking combined oral estrogen–progestin replacement do not experience an increased risk of ovarian cancer. They do experience a slightly increased risk of developing asthma.

Progestins may cause moodiness, particularly in women with a history of premenstrual dysphoric disorder. Cycled progestins may trigger migraines in certain women. Many other adverse reactions have been reported, including breast tenderness, alopecia, and fluid retention. Contraindications to the use of progestins include thromboembolic disorders, liver disease, breast cancer, and pregnancy.

Hormone Replacement Therapy (HRT): Agents

Hormone replacement needs to be individualized. Ideally, in women with an intact uterus, very low-dose transdermal estradiol may be used alone or with intermittent progestin or a progesterone-eluting intrauterine device, in order to reduce the risk of endometrial hyperplasia, while avoiding the need for daily oral progestin. Vaginal estrogen can be added if low-dose systemic estradiol replacement is insufficient to relieve symptoms of vulvovaginal atrophy. Women who have had a hysterectomy may receive transdermal estrogen at whatever is the lowest dose that adequately relieves symptoms. However, some women cannot find sufficient relief with transdermal estradiol and must use an oral preparation.

Transdermal estradiol –

Estradiol can be delivered systemically with different systems of skin patches, mists, or gels.  Transdermal estradiol works for most women, but some women have poor transdermal absorption. If a woman has a skin reaction to an estradiol patch, then a gel or mist may be tried at different doses until the ideal formulation is found.

A. Estradiol patches mixed with adhesive: These systems tend to cause minimal skin irritation. Generic estradiol transdermal is available as a patch that is replaced biweekly (0.025, 0.0375, 0.05, 0.075, 0.1 mg/d) or weekly (0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 mg/day). Brand products include: Vivelle-Dot (0.025) or Minivivelle (0.0375, 0.05, 0.075, or 0.1 mg/day) or Alora (0.025, 0.05, 0.075, or 0.1 mg/day), replaced twice weekly; Climara (0.025, 0.0375, 0.05, 0.06, 0.075, or 0.1 mg/day), replaced weekly; and Menostar (0.014 mg/day), replaced weekly. This type of estradiol skin patch can be cut in half and applied to the skin without proportionately greater loss of potency. Minivivelle patches are the smallest.

B. Estradiol gels, lotions, and mists:   EstroGel 0.06% is available in a metered-dose pump that dispenses 1.25 g gel per actuation (dose: half to 2 actuations/day). Elestrin 0.06% is available in a metered-dose pump that dispenses 0.87 g gel per activation (dose: half to 2 actuations/day). These gels are applied daily to one arm from the wrist to the shoulder after bathing. Divigel 0.1% gel (0.25, 0.5, 1 g/packet) is applied to the upper thigh daily.  Estrasorb 2.5% is available in 1.74 g pouches (4.35 mg estradiol); 1 – 2 pouches of lotion are applied to the thigh/calf daily.  Evamist is available as a topical mist dispenser that dispenses 1.53 mg estradiol/spray; sprays are applied to the inner forearm daily; a single daily spray may provide sufficiently low-dose estradiol to possibly obviate the need for daily progestin in women with an intact uterus. To avoid spreading topical estradiol to others, the hands should be washed and precautions taken to avoid prolonged skin contact with children. Application of sunscreen prior to estradiol gel has been reported to increase the transdermal absorption of estradiol.

C. Patches with both estradiol and progestin mixed with adhesive:  These preparations mix estradiol with either norethindrone acetate or levonorgestrel. Combipatch (0.05 mg E with 0.14 mg norethindrone acetate daily or 0.05 mg E with 0.25 mg norethindrone acetate daily) is replaced twice weekly. Climara Pro (0.045 mg E with 0.015 mg levonorgestrel daily) is replaced once weekly. The addition of a progestin reduces the risk of endometrial hyperplasia, but breakthrough bleeding occurs commonly. The combined patch increases the risk of breast cancer. Scalp hair loss, acne, weight gain, skin reactions, and poor skin adherence have been reported with these patches.

Oral estrogen –

A. Oral estrogen-only preparations:  These preparations include conjugated equine estrogens that are available as Premarin (0.3, 0.45, 0.625, 0.9, and 1.25 mg), conjugated plant-derived estrogens (eg, Menest, 0.3, 0.625, and 2.5 mg), and conjugated synthetic estrogens that are available as Cenestin (0.3, 0.45, 0.625, 0.9, and 1.25 mg) and Enjuvia (0.3, 0.45, 0.625, 0.9, and 1.25 mg). Other preparations include estradiol (0.5, 1, and 2 mg), and estropipate (0.75, 1.5, and 3 mg).


B. Oral estrogen plus progestin preparations:  Conjugated equine estrogens with medroxyprogesterone acetate is available as Prempro (0.3/1.5, 0.45/1.5, 0.625/2.5, and 0.625 mg/5 mg); conjugated equine estrogens for 14 days cycled with conjugated equine estrogens plus medroxyprogesterone acetate for 14 days is available as Premphase (0.625/0, then 0.625 mg/5 mg); estradiol with norethindrone acetate (0.5/0.1 and 1 mg/0.5 mg); ethinyl estradiol with norethindrone acetate is available as Femhrt (2.5/0.5 and 5 mcg/1 mg) and Jinteli (5 mcg/1 mg); estradiol with drospirenone is available as Angeliq (0.5 mg/0.25 mg, and 1.0 mg/0.5 mg); estradiol with norgestimate is available as Prefest (estradiol 1 mg/day for 3 days, alternating with 1 mg estradiol/0.09 mg norgestimate daily for 3 days). Oral contraceptives can also be used for combined HRT.

Vaginal estrogen –

Urogenital atrophy commonly develops in postmenopausal women and can cause dryness of the vagina, genital itching, burning, dyspareunia, and recurrent urinary tract infections. Urinary symptoms can include urgency and dysuria. Vaginal estrogen is intended to deliver estrogen directly to local tissues and is moderately effective in reducing these symptoms, while minimizing systemic estrogen exposure. Some estrogen is absorbed systemically and can relieve menopausal symptoms. Manufacturers recommend that these preparations be used for only 3–6 months in women with an intact uterus, since vaginal estrogen can cause endometrial proliferation. However, most clinicians use them for longer periods. Vaginal estrogen can be administered in three different ways: creams, tablets, and rings.

A. Estrogen vaginal creams:  These creams are administered intravaginally with a measured-dose applicator daily for weeks for atrophic vaginitis, then administered one to three times weekly. Available preparations include conjugated equine estrogens, which is available as Premarin Vaginal (0.625 mg/g cream), dosed as 0.25–2 g cream administered vaginally one to three times weekly. Estradiol is available as Estrace Vaginal (0.1 mg/g cream), 1 g cream administered vaginally one to two times weekly.

B. Estradiol vaginal tablets: These tablets are sold prepackaged in a disposable applicator and can be administered deep intravaginally daily for 2 weeks for atrophic vaginitis, then twice weekly. The tablets dissolve into a gel that gradually releases estradiol. This preparation is available as Vagifem (10 mcg/tablet), administered vaginally two times weekly.

C. Estradiol vaginal rings: These rings are inserted manually into the upper third of the vagina, worn continuously, and replaced every 3 months. Variable amounts of the released estradiol enters the systemic circulation. Vaginal rings do not usually interfere with sexual intercourse. If a ring is removed or descends into the introitus, it may be washed in warm water and reinserted. Estring (2 mg estradiol/ring) releases estradiol 7.5 mcg/day with only 8% entering the systemic circulation, resulting in mean serum estradiol concentrations of only about 10 pg/mL; it is most effective for local vaginal symptoms.  Femring releases estradiol acetate that is quickly hydrolyzed to estradiol and is available in two strengths: 12.4 mg/ring releases estradiol acetate 0.05 mg/day or 24.8 mg/ring releases estradiol acetate 0.1 mg/d, resulting in mean serum estradiol concentrations of about 40 pg/mL and 80 pg/mL, respectively; it is effective for both systemic and local vaginal symptoms.  Both rings are replaced every 90 days. For women with postmenopausal urinary urgency and frequency, even the low-dose Estring can successfully reduce urinary symptoms.

D. Estradiol with progestin vaginal rings:  The available preparation in NuvaRing that releases a mixture of ethinyl estradiol 0.015 mg/day and etonogestrel 0.12 mg/day. It is a contraceptive vaginal ring that is placed in the vagina on or before day 5 of the menstrual cycle, left for 3 weeks, removed for 1 week, and then replaced.

Estradiol injections –

Parenteral estradiol should be used only for particularly severe menopausal symptoms when other measures have failed or are contraindicated. Estradiol cypionate (Depo-Estradiol 5 mg/mL) may be administered intramuscularly in doses of 1–5 mg every 3–4 weeks. Estradiol valerate (20 or 40 mg/mL) may be administered intramuscularly in doses of 10–20 mg every 4 weeks. Women with an intact uterus should receive a progestin for the last 10 days of each cycle.

Oral progestins –

For a woman with an intact uterus, long-term conventional-dose unopposed systemic estrogen therapy can cause endometrial hyperplasia, which typically results in dysfunctional uterine bleeding and might rarely lead to endometrial cancer. Progestin therapy transforms proliferative into secretory endometrium, causing a possible menses when given intermittently or no bleeding when given continuously.

The type of progestin preparation, its dosage, and the timing of administration may be tailored to the given situation. Progestins may be given daily, monthly, or at longer intervals. When given episodically, progestins are usually administered for 7–14 day periods. Bedtime administration may improve sleep. Some women find that progestins produce adverse effects, such as irritability, nausea, fatigue, or headache; long-term progestins given with estrogen replacement increase the risk for breast cancer.

Oral progestins are available in different formulations: Micronized progesterone (100 mg and 200 mg/capsule), medroxyprogesterone (2.5, 5.0, and 10 mg/tablet), norethindrone acetate (5 mg/tablet), and norethindrone (0.35 mg/tablet). Topical progesterone (20–50 mg/day) may reduce hot flushes in women who are intolerant to oral HRT. It may be applied to the upper arms, thighs, or inner wrists daily. It may be compounded as micronized progesterone 250 mg/mL in a transdermal gel. Its effects upon the breast and endometrium are unknown. Progesterone is also available as vaginal gels (eg, Prochieve, 4% = 45 mg/applicatorful, and 8% = 90 mg/applicatorful) that are typically given for secondary amenorrhea and administered vaginally every other day for six doses.

Progestin-releasing intrauterine devices –

Intrauterine devices that release progestins can be useful for women receiving ERT, since they can reduce the incidence of dysfunctional uterine bleeding and endometrial carcinoma without exposing women to the significant risks of systemic progestins. The Mirena intrauterine device releases levonorgestrel and is inserted into the uterus by a clinician within 7 days of the onset of menses. It is equally effective at reducing endometrial hyperplasia as cycled medroxyprogesterone acetate and is associated with less hirsutism. It remains effective for up to 5 years. Parous women are generally better able to tolerate the Mirena intrauterine device than nulliparous women.

Selective estrogen receptor modulators (SERMs) –

SERMs (eg, raloxifene, ospemifene, tamoxifen) are an alternative to estrogen replacement for hypogonadal women at risk for osteoporosis who prefer not to take estrogens because of their contraindications (eg, breast or uterine cancer) or side effects.  Raloxifene (Evista) does not reduce hot flushes, vaginal dryness, skin wrinkling, or breast atrophy; it does not improve cognition. However, in doses of 60 mg/day orally, raloxifene inhibits bone loss without stimulating effects upon the breasts or endometrium. Raloxifene does not stimulate the endometrium and actually reduces the risk of endometrial carcinoma, so concomitant progesterone therapy is not required. Another advantage to raloxifene is that it reduces the risk of invasive breast cancer by about 50%. Raloxifene slightly increases the risk of venous thromboembolism (though less so than tamoxifen), so it should not be used by women at prolonged bed rest or otherwise prone to thrombosis. Ospemifene (Osphena) is a SERM that has unique estrogen-like effects on the vaginal epithelium and is indicated for the treatment of postmenopausal dyspareunia when other therapies are ineffective. Given orally in doses of 60 mg/day, it commonly aggravates hot flushes, increases the risks of thromboembolism, and increases endometrial hyperplasia. Ospemifene has unknown long-term effects upon bone and breast.  Therefore, I have never seen a reason to prescribe it.

Tibolone (Livial) is an SERM whose metabolites have mixed estrogenic, progestogenic, and weak androgenic activity. It is comparable to HRT for the treatment of climacteric-related complaints. It does not appear to significantly stimulate proliferation of breast or endometrial tissue. It depresses both serum triglycerides and HDL cholesterol. Long-term studies are lacking. It is not available in the United States.

Testosterone replacement for women –

In premenopausal women, serum testosterone levels decline with age. Between 25 and 45 years of age, women’s testosterone levels fall 50%. After natural menopause, the ovaries remain a significant source for testosterone and serum testosterone levels do not fall abruptly. In contrast, very low serum testosterone levels are found in women after bilateral oophorectomy, autoimmune ovarian failure, or adrenalectomy, and in hypopituitarism. Testosterone deficiency contributes to hot flushes, loss of sexual hair, muscle atrophy, osteoporosis, and diminished libido, also known as hypoactive sexual desire disorder. Flibanserin (Addyi) is a centrally acting drug that stimulates serotonin 5-HT1A receptors and blocks other brain receptors.  Flibanserin is modestly effective for treating premenopausal women with acquired hypoactive sexual desire disorder. It is administered orally 100 mg at bedtime; side effects may include hypotension, appendicitis, nausea, xerostomia, sleep disorders, and fatigue.  If there is no improvement within 8 weeks, it is discontinued.

In women, diminished libido is common and multifactorial. Although low serum testosterone levels may contribute to hypoactive sexual desire disorder, hysterectomy and sexual isolation are major causes. Low serum testosterone levels may also cause fatigue, a diminished sense of well-being, and a dulled enthusiasm for life. Androgen replacement may improve these problems.

Selected women may be treated with low-dose testosterone. Oral methyltestosterone can be compounded into capsules and taken orally in doses of 1.25 – 2.5 mg daily. Methyltestosterone also is available combined with esterified estrogens: 1.25 mg methyltestosterone/0.626 mg esterified estrogens or 2.5 mg methyltestosterone/1.25 mg esterified estrogens. The latter formulations are convenient but carry the same disadvantages as oral estrogen—particularly an increased risk of thromboembolism.  Topical testosterone can also be compounded as a cream containing 1 mg/mL, with 1 mL applied to the abdomen daily.

Women receiving testosterone therapy must be monitored for the appearance of any acne or hirsutism, and serum testosterone levels are determined periodically if women feel that they are benefitting and long-term testosterone therapy is instituted. Side effects of low-dose testosterone therapy are usually minimal but may include erythrocytosis, emotional changes, hirsutism, acne, an adverse effect on lipids, and potentiation of warfarin anticoagulation therapy. Testosterone therapy tends to reduce both triglyceride and HDL cholesterol levels. Hepatocellular neoplasms and peliosis hepatis, rare complications of oral androgens at higher doses, have not been reported with oral methyltestosterone doses of 2.5 mg or less daily.

Vaginal testosterone is an option for postmenopausal women who cannot use systemic or vaginal estrogen due to breast cancer. Testosterone 150 – 300 mcg/day vaginally appears to reduce vaginal dryness and dyspareunia without increasing systemic estrogen levels.

Caution: Androgens should not be given to women with liver disease or during pregnancy or breastfeeding. Testosterone replacement therapy for women should be used judiciously, since long-term prospective clinical trials are lacking. An analysis of the Nurses’ Health Study found that women who had been taking conjugated equine estrogens plus methyltestosterone experienced an increased risk of breast cancer, so breast cancer screening is recommended.


REFERENCES:  (To view an abstract, go to  and plug in the PMID number.)

Behnamfar F et al.  Levonorgestrel-releasing intrauterine system (Mirena) in compare to medroxyprogesterone acetate as a therapy for endometrial hyperplasia.  J Res Med Sci. 2014 Aug;19(8):686-90 [PMID: 25422650]

Benkhadra K et al. Menopausal hormone therapy and mortality: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Nov;100(11):4021-8. [PMID: 26544652]

Bergendal A et al. Risk of venous thromboembolism associated with local and systemic use of hormone therapy in peri- and postmenopausal women and in relation to type and route of administration. Menopause. 2016 Jun;23(6):593-9. [PMID: 27023862]

Cherry N et al. Long-term safety of unopposed estrogen used by women surviving myocardial infarction: 14-year follow-up of the ESPRIT randomized controlled trial. BJOG. 2014 May;121(6):700-5. [PMID: 24533510]

Gurney EP et al. The Women’s Health Initiative trial and related studies: 10 years later: a clinician’s view. J Steroid Biochem Mol Biol. 2014 Jul;142:4–11. [PMID: 24172877]

Joffe H et al. Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial. JAMA Intern Med. 2014 Jul;174(7):1058-66. [PMID: 24861828]

Klein DA et al. Amenorrhea: an approach to diagnosis and management. Am Fam Physician. 2013 Jun 1;87(11):781-8. [PMID: 23939500]

Lovre D et al. Effect of menopausal hormone therapy on components of the metabolic syndrome. Ther Adv Cardiovasc Dis. 2016 May:Epub. [PMID: 27234158]

Manson JE, Kaunitz AM. Menopause management’s getting clinical care back on track. N Engl J Med. 2016 Mar;374(9):803-6. [PMID: 26962899]

Mohammed K et al. Oral vs transdermal estrogen therapy and vascular events: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Nov;100(11):4012-20. [PMID: 26544651]

Nelson HD et al. Menopausal hormone therapy for the primary prevention of chronic conditions: a systematic review to update the U.S. Preventive Services Task Force recommendations. Ann Intern Med. 2012 Jul 17;157(2):104-13. [PMID: 22786830]

Schmidt PJ et al. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry. 2015 Jul;72(7):714-26. [PMID: 26018333]

Shifren JL. Testosterone for midlife women: the hormone of desire? Menopause. 2015 Oct;22(10):1147-9. [PMID: 26397145]

Stuenkel CA et al. Treatment of symptoms of the menopause: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015 Nov;100(11):3975-4011. [PMID: 26444994]



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Hemoglobin A1c Testing

Hemoglobin A1c: Hemoglobin is composed of a tetramer of globin chains; two of the chains are alpha-globin (chromosome 16). Most adults have hemoglobin that is largely comprised of two alpha chains combined with two beta chains (chromosome 11) (alpha2beta2), called HbA. The exons that encode beta-globin are adjacent to those encoding delta-globin and gamma-globin. About 2% of most adults’ hemoglobin is a variant (alpha2delta2), called HbA2. Less than 1% of most adults’ hemoglobin in fetal hemoglobin (alpha2gamma2), called HbF. A portion of HbA becomes glycosylated during its formation; a stable variety of glycosylated hemoglobin is called HbA1c.

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Acromegaly & Gigantism

Acromegaly refers to the clinical syndrome caused by excessive growth hormone (GH) in adulthood, after the closure of epiphyses (bone growth plates). GH produces many of its effects through the stimulation of insulin-like growth factor (IGF-I), produced in the liver and at epiphyses. Symptoms of acromegaly typically include the growth of hands and feet, the growth of jaw and brow, with coarsening of facial features. Bones grow thicker and the growth of spinal bone can cause spinal stenosis and serious neurologic problems. Affected individuals are usually very sweaty, and also have increased muscle mass and reduced subcutaneous fat. Carpal tunnel syndrome is common. Diabetes and hypertension commonly occur. Untreated patients have a reduced life expectancy due to cardiovascular complications.

Gigantism refers to excessive growth in stature during childhood and adolescence, caused by excessive growth hormone. Affected children are much taller than expected for their age. Without treatment, such children eventually develop acromegaly in addition to their gigantism.

In patients with acromegaly or gigantism, a pituitary adenoma (tumor) produces excessive amounts of GH. Such pituitary adenomas are generally benign, but they may grow such that they can impinge upon the optic chiasm (the crossing and recombination of the optic nerves) that is located just superior to the pituitary; such impingement can cause visual field defects. GH-secreting pituitary adenomas can also invade the cavernous sinuses that border the pituitary laterally; since the cavernous sinuses harbor veins, cranial nerves, and the carotid artery, pituitary tumors that have invaded a cavernous sinus are considered unresectable.

Diagnosis: When acromegaly or gigantism is suspected, it must be diagnosed with hormonal testing. Following an overnight fast, a serum specimen is obtained and assayed for prolactin, IGF-I, glucose, AST, BUN, phosphorus, TSH and free thyroxine. Glucose syrup 75 g is then given orally and serum GH is measured 60 minutes later. Acromegaly is excluded if the serum GH is less than 1 mcg/L (IRMA or chemiluminescent assays) or less that 2 mcg/dL (older radioimmunoassays) after glucose syrup, and if the IGF-I is normal. The IGF-I should be assayed at a reputable laboratory. Misleadingly high serum GH levels can be caused by exercise or eating just before the test, acute agitation or illness, renal or hepatic failure, malnourishment, diabetes mellitus, or concurrent treatment with clonidine, beta-blockers, or estrogens.

Magnetic resonance imaging (MRI) of the pituitary is obtained after the biochemical confirmation of acromegaly. The MRI is quite sensitive (about 90%) in identifying a GH-secreting pituitary adenoma.

Treatment: The best treatment for patients with a GH-secreting pituitary adenoma is transsphenoidal pituitary surgery by a skilled neurosurgeon. The surgical incision is ordinally in the inner nose or under the upper lip. A skilled surgeon can ordinarily identify and resect the pituitary tumor while leaving the normal pituitary gland in place. After the successful selective resection of a pituitary adenoma, pituitary funcion usually remains intact. After successful surgery, patients notice an immediate improvement in sweatiness and carpal tunnel syndrome. However, bone enlargement in permanent.

After pituitary surgery, patients must be followed regularly: clinically and with serial serum GH and IGF-I levels. Persistent or recurrent elevations in serum GH and IGF-I levels indicate the presence of residual tumor tissue in the pituitary, cavernous sinuses, or surrounding bone. Pituitary re-exploration may be warranted, if the recurrent tumor can be visualized on MRI and appears resectable. Otherwise, alternate treatment strategies are warranted: Oral cabergoline may be successful, particularly for patients whose pituitary tumor co-secretes prolactin along with GH. Another option is octreotide, which inhibits the secretion of GH from the tumor; it is ordinarily given by injection monthly. Pegvisomant is given by injection and inhibits the effect of GH at the GH receptors in tissues, thereby reducing GH effect. Some patients may require radiation therapy, but conventional radiation therapy typically causes hypopituitarism and long-term cognition changes. Therefore, better-focussed radiation is preferrable, when possible; gamma-knife and cybersknife are advanced radiation therapy techniques that can focus radiation therapy more accurately into recurrent tumor tissue.

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Hyperparathyroidism therapy with cinacalcet

The tiny parathyroid glands are located in the neck and are usually located adjacent to the thyroid gland, hence the term “parathyroid”. There are usually four parathyroid glands, but there can be more, and they can sometimes lie in locations away from the thyroid, sometimes elsewhere in the neck or even in the chest (mediastinum).

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Introduction to Pheochromocytoma and Paraganglioma

Pheochromocytomas are uncommon tumors that arise from cells of the sympathetic nervous system and may secrete catecholamines (adrenalin). Such tumors are usually found within one or both adrenal glands (90%), but may arise in other areas of sympathetic nerve cells, and are then called paragangliomas. About 10% are found to be malignant at the time or immediately after the primary tumor is discovered. Another 5% of individuals with pheochromocytomas are later found to have malignant or recurrent disease. Interestingly, about 10% of such patients do not have hypertension at all or may have hypertension only during surgical procedures or very intermittently at which time a hypertensive crisis can occur.

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5 Questions and Answers on Male Hypogonadism and Testosterone Deficiency

Male Hypogonadism (testosterone deficiency) is a hormone disorder in which the body does not produce enough testosterone. This condition affects 10% of all adult men and the majority of men over age 80 years.

This post will review the symptoms, causes, and treatments of male hypogonadism, and will answer some typical questions from patients with this condition.

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Hypothyroidism: Diagnosis & Treatment

Google and the UCSF Department of Medicine commissioned me to write a Google Knol entitled “Hypothyroidism.” I’ve included sections of it here.

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Due to the COVID-19 pandemic, I’ve been practicing telemedicine along with in-office appointments.

Asymptomatic individuals frequently transmit the SARS-COV-2 virus to others, which can result in serious morbidity and mortality.  Therefore, our office is abiding by UCSF guidelines and practicing telemedicine whenever possible.  We request that anyone who is ill and coming for an in-person visit, please check themselves for COVID-19 with a home antigen test beforehand.

To make a telemedicine appointment, email us at or call 415-665-1136.  To prepare for the appointment, we’ll email you a telemedicine protocol, so that you can prepare and derive the most benefit from your virtual visit.  It’s been working out ably well and many patients find it more convenient.


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Journal of Clinical Oncology Paper

This paper was published in the Journal of Clinical Oncology in September, 2009. My colleagues and I describe our experience treating 50 patients with high-dose 131I-MIBG for their malignant pheochromocytoma or paraganglioma.

Phase II Study of High-Dose [131I]Metaiodobenzylguanidine Therapy for Patients With Metastatic Pheochromocytoma and Paraganglioma (PDF)

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Embolization of a large secretory paraganglioma

My colleagues and I presented two papers at the Second International Symposium on Pheochromocytoma at Queens College, Cambridge University in October 2008.  We describe the successful pre-operative embolization of a large secretory paraganglioma.

Poster: Embolization of a large secretory paraganglioma (PDF)

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