Congenital adrenal hyperplasia (CAH)

PerkinElmer's Neonatal17 a-OH-Progesterone (17OHP) assay for its DELFIA®, AutoDELFIA® and GSP® platforms platforms provides the highest standards of reliability and safety in screening for congenital adrenal hyperplasia (CAH). It is globally the most widely used assay for 1st tier CAH screening, and in 2008 theproduct was used in 47 countries.

No extraction step needed

The assay is a straightforward dried blood spot assay.  No extraction step is needed, which means savings in both total assay time and materials.

DELFIA®-technology stands for quality

The unique fluorescent properties of lanthanide chelatesare the basis for high sensitivity and low assay variation, and these features, in turn, stand for reliable and accurate 17a-OH-Progesterone measurement with low bias.

Early diagnosis for early disease/Intervention

Congenital adrenal hyperplasia is a genetic disorder affecting 1:10,000 to 1:15,000 newborns worldwide and the most severe form of the disease can lead to a life-threatening condition during the first weeks of life.  The disease is caused by enzyme defects in the steroid biosynthesis, the most frequent types being 21- and 11a-hydroxylase deficiency. In both of these the17a-OH-progesterone, a precursor for cortisol, is increased which makes its determination a useful screening method for 95% of all of the CAH cases.

PerkinElmer's Neonatal 17OHP assay is intended for the quantitative determination of 17a-OH-progesterone indried blood spot specimens as an aid in screening newborns for CAH.

From http://www.perkinelmer.com/Catalog/Category/ID/Congenital%20adrenal%20hyperplasia%20CAH

CAH (congenital adrenal hyperplasia) and Prenatal Dexamethasone

MountainQueen posted this on the Cushing's Help Boards.  She said:

I came across this article about the clinical use of Dex for CAH carriers. After reading this article I remembered that NO ONE asked me if I was pregnant before I took the Dex test. What would have happened if I had been?
Very interesting article for CAH gene carriers: From Time Magazine on line

Medical Ethics: Prenatal Dexamethasone Use Questioned

By CATHERINE ELTON Catherine Elton – Mon Jun 21, 11:45 pm ET

When Marisa Langford found out she was pregnant again, she called Dr. Maria New, a total stranger, before calling her own mother. New, a prominent pediatric endocrinologist and researcher at Mount Sinai Medical Center in New York City, is one of the world's foremost experts in congenital adrenal hyperplasia, or CAH, a group of inherited disorders of the adrenal gland.

Langford and her husband learned they were silent carriers of the genetic variation that causes CAH when their son was diagnosed with the condition after birth. Their son - like the 1 in 16,000 babies born with CAH each year in the U.S. - faces a lifetime of taking powerful steroid medications to compensate for his faulty adrenal glands. When Langford contacted New about her second pregnancy, New, who was not Langford's regular doctor, called a local pediatric endocrinologist. That doctor prescribed Langford a commonly used medication for CAH. "Dr. New told me I had to start taking dexamethasone immediately," says Langford, 30, who lives in Tampa. "We felt very confident in someone of her stature and that what she was telling us was the right thing to do."(See the most common hospital mishaps.)

The early prenatal use of dexamethasone, or dex, has been shown to prevent some of the symptoms of CAH in girls, namely ambiguous genitalia. Because the condition causes overproduction of male hormones in the womb, girls who are affected tend to have genitals that look more male than female, though internal sex organs are normal. (In boys, in contrast, the condition leads to early signs of puberty, such as deep voice, body hair and enlarged penis by age 2 or 3.) But while the prenatal treatment may address girls' physical symptoms, it does not prevent the underlying, medical condition, which in some severe cases can be life-threatening, nor does it preclude the need for medication throughout life.

Langford says also that neither New nor her prescribing physician mentioned that prenatal dexamethasone treatment is an off-label use of the drug (an application for which it was not specifically approved by the government) or that the medical community is sharply divided over whether dexamethasone should be used during pregnancy at all.

Is It Safe - or Even Necessary?
To date, there has been just one controlled, prospective, long-term trial of prenatal dexamethasone for the prevention of ambiguous genitalia, conducted in Sweden. The results, published in 2007 in the Journal of Clinical Endocrinology & Metabolism - more than two decades after doctors began using the medication in pregnant patients - found some mild behavioral and cognitive deficits in children whose mothers had been treated. But the study, with just 26 participants, was too small to be definitive. "We just don't know what we are doing to these kids," says Dr. Walter Miller, the chief of endocrinology at University of California, San Francisco. "It's not sufficient to say, The baby was born and had all fingers and toes, so it's fine."(See the top 10 medical breakthroughs of 2009.)

In animal studies, dexamethasone has been shown to cause birth defects, but proponents of the treatment note that no human birth defects have ever been associated with the treatment, and that it is uncertain whether findings in lab animals translate to humans. Meanwhile, the possible benefits are clear: the treatment can spare young girls the potential psychosocial problems associated with having ambiguous genitalia as well as the ordeal of surgery to correct deformities later. "I see potential for benefits and I don't see evidence there's any negatives to this. There are lots of risks associated with surgery, and if this can prevent surgery, then it's a good thing," says Dr. Ingrid Holm, a pediatric endocrinologist at Children's Hospital in Boston.

Research has also suggested that affected women who were treated with dex in the womb show more typical gender behavior than other women with CAH; the latter group tends to behave more tomboyishly and express little interest in having children. New told the Wall Street Journal in 2009 that the treatment further spares parents the "terrifying prospect" of not knowing whether their newborn is a boy or a girl. (Comment on this story.)

It is these very benefits, however, that lead some researchers to question what, exactly, doctors are treating - and whether it needs to be treated at all. Miller believes that prenatal dex is being used to alleviate "parental anxiety," rather than the child's condition. Other doctors and researchers have criticized New for introducing gender behavior into the medical prognosis - in two recent presentations on CAH at medical conferences, New offered medical outcome data on prenatal dex alongside data on typical gender behavior. "Maybe this gives clinicians the idea that the treatment goal is normalizing behavior. To say you want a girl to be less masculine is not a reasonable goal of clinical care," says David E. Sandberg, a University of Michigan pediatric psychologist who treats and conducts research on children with CAH.(Read how postpartum depression can strike fathers.)

Perhaps most controversially, prenatal dex must be given as soon as a woman learns she is pregnant, which is usually several weeks before genetic tests can determine if the fetus is in fact a female affected with CAH - the chance of which is 1 in 8 for parents who already have an affected child or know they are carriers of the genetic disorder. If the baby is healthy, treatment is stopped, but at that point, the fetus has been exposed to the steroid drug for weeks. There is no data on how many mothers receive prenatal dex, but according to the odds, 7 of 8 may be taking medication unnecessarily.

Concerns over Patient Consent
Some critics strongly oppose prenatal dex in large part because of the way it is presented to patients. Guidelines issued by pediatric endocrine societies in Europe and North America recommend that doctors obtain written informed consent from the patient as well as ethics-committee oversight for the treatment, but it is not known how many physicians adhere to these guidelines. Langford says she was not made aware of them. In addition, 2010 practice guidelines from the international Endocrine Society suggest that prenatal dex be administered as part of clinical research, which requires informed consent and ethics-committee oversight.

However, prenatal dex is routinely given outside the research setting, as an off-label treatment. It is common - and perfectly legal - for doctors to use their own discretion when prescribing drugs off-label. Antiseizure drugs like topiramate are commonly prescribed to treat migraine headache pain, for example. The practice allows patients to receive valuable treatment for which the drug may not have been expressly approved and may never be - it takes money and drug-company interest, which are hard to come by, to conduct the large randomized controlled trials required for a new-use the Food and Drug Administration (FDA) approval of a drug that is already on the market.

But as doctors share information about a drug's perceived off-label benefits and lack of harm, it gets even harder to take a step back and launch a formal randomized controlled trial - considered the gold standard in medical research - because patients demand the treatment, and doctors say it would be unethical to withhold it from them or from control groups in clinical trials. "It's a risky and dangerous way to innovate," says prominent University of Pennsylvania bioethicist Arthur Caplan. "There's no systematic collection of information. So, yes, things do get proven this way, and it is a way to innovate, but it also can come at a cost of unnecessary expense and, sometimes, bad side effects."

It also enables doctors to do human research without gaining proper approval. All participants in human medical research are, by law, entitled to the protective oversight of an institutional review board (IRB), a committee that safeguards the interests of research volunteers and ensures they have been fully informed about the potential risks and benefits of an experimental treatment. If doctors are simply treating a patient with an off-label drug, they are not required to obtain written informed consent from patients. But if doctors give treatment with the intent to gain knowledge, they are technically doing research, which must receive IRB approval.

Ethicists say physicians may sometimes treat patients off-label, then decide later to launch a follow-up study; or, they do follow-up research on patients who have been treated by other doctors. In the process, they have converted these patients into unwitting research volunteers. Some doctors game the system this way, Caplan says, to avoid battles with IRBs.

Critics suspect that Mount Sinai's New, who has long championed prenatal dex and bills it as safe on her foundation website, has gamed the system. In a letter dated Feb. 2, 2010, a group of 36 bioethicists, including Alice Dreger, a professor of bioethics at Northwestern University, asked the FDA and the federal Office for Human Research Protections to investigate New's practices; the authors contend that the doctor has conducted follow-up studies on prenatal dex patients without receiving IRB approval for treatment trials. Dreger says she has also asked Weill Cornell Medical College, where New previously worked, and Mount Sinai Medical Center to investigate the matter.

New, who declined to be interviewed for this article, does not administer the treatment in her current practice - according to Mount Sinai Medical Center, she has prescribed it only once since joining the hospital in 2004 - but ethical concerns remain, Dreger says, if the doctor consults with patients, resulting in their being prescribed dex elsewhere, then follows up with them for research purposes. At a medical conference in January, where New presented data from her research on prenatal dex, the doctor refused to answer a fellow researcher's questions regarding her process of informed consent.

Clinical Trials vs. Legal Trials
For Langford's part, she says she is grateful to New for her help, even though her daughter, now 4 and healthy, was found not to have CAH.

But Jenny Westphal, 24, who took dexamethasone throughout her pregnancy at the recommendation of another doctor, says she feels misled. Like Langford she was not asked to give informed consent. Unlike Langford, however, her daughter, now 3, who has CAH, has also had serious and mysterious health problems since birth, including feeding disorders, that are not commonly associated with her adrenal-gland disorder.

In April, Westphal, who lives in Wisconsin, started doing research online and discovered there was some controversy over the treatment. "I was outraged, frustrated and confused. Confused, because no one had ever warned me about this. I wasn't given the chance to decide for myself, based on the risks and benefits, if I wanted the treatment or not," she says.

Westphal may never know whether her daughter's problems were caused by dexamethasone, though she will likely always believe they were. That is why so many similar situations, in which experimental drugs are prescribed off-label without informed consent rather than in clinical trials, wind up becoming case studies - not in scientific journals, but exactly where Westphal and her husband are considering taking theirs: to court.

Originally from http://news.yahoo.com/s/time/20100622/hl_time/08599199645300

Update on the management of hirsutism

doi: 10.3949/ccjm.77a.08079    Cleveland Clinic Journal of Medicine  June 2010   vol. 77  6  388-398 

   1.  SHANNON HARRISON, MBBS, MMed, FACD*

   1.  NAJWA SOMANI, MD

   1.  WILMA F. BERGFELD, MD?

ADDRESS: Wilma F. Bergfeld, MD, Dermatology and Plastic Surgery Institute, A61, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail bergfew@ccf.org.

EDUCATIONAL OBJECTIVE: Readers will recognize signs of androgen excess and will consider current treatment options for hirsutism

 

Abstract

Hirsutism is a source of significant anxiety in women. While polycystic ovary syndrome or other endocrine conditions are responsible for excess androgen in many patients, other patients have normal menses and normal androgen levels (“idiopathic” hirsutism). The goal of the evaluation is to rule out any underlying pathology. The goals of therapy are to treat any underlying condition and to remove the excess hair. Current options for hair removal are discussed. Educating patients so they have reasonable treatment expectations is essential, as significant improvement may take weeks or months, and treatment may need to be repeated on an ongoing basis.

Key points

The finding of polycystic ovaries is not required for the diagnosis of polycystic ovary syndrome, nor does their presence prove the diagnosis. Gonadotropin-dependent functional ovarian hyperandrogenism is believed to cause this syndrome; however, mild adrenocorticotropic-dependent functional adrenal hyperandrogenism also is a feature in many cases.

Even women with mild hirsutism with subtle symptoms and signs of hyperandrogenism can have elevated androgen levels, and thus, they deserve a laboratory evaluation.

Laser treatment does not result in complete, permanent hair reduction, but it is more effective than shaving, waxing, and electrolysis, producing partial hair reduction for up to 6 months.

• ↵* Dr. Harrison received funding in 2008 from the F.C. Florance Bequest, administered through the Australasian College of Dermatologists.

Hirsutism causes significant anxiety and lack of self-esteem in women. Although it is itself a benign condition, it is often the sign of an underlying and possibly serious endocrine condition.

As we will discuss, the diagnosis begins with a detailed history and physical examination, with laboratory testing and imaging as needed to confirm or rule out underlying causes. Management begins with patient education and support and includes hair removal and drug treatment of any underlying metabolic derangement.

PREVALENCE AND IMPACT

Hirsutism is a common disorder of excess growth of terminal hair in an androgen-dependent male distribution in women, including the chin, upper lip, breasts, upper back, and abdomen.¹ It affects 5% to 10% of women of reproductive age.^1,2

Hirsutism should be differentiated from hypertrichosis, which can be hereditary or acquired, and which is defined as increased general hair growth in androgen-independent areas.¹

Excess hair is cosmetically concerning for women and can significantly affect self-esteem. ³ Normal or acceptable hair growth depends on a woman’s ethnicity and her perception of familial, cultural, and societal norms for the quantity and distribution of hair. Mediterranean women generally have a medium amount of body and facial hair, whereas Asian women have a minimal amount.^1,4,5

Hirsutism can be clinically graded according to the Ferriman-Gallwey scale^2,6 and is defined as a Ferriman-Gallwey score of 8 or higher.¹

HOW CIRCULATING ANDROGENS AFFECT HAIR FOLLICLES

In androgen-dependent areas, circulating androgens influence hair follicle characteristics. Androgens increase the size and diameter of the hair fibers in certain androgen-dependent sites, as seen in puberty with the transformation of vellus hairs (small, nonpigmented hairs) into terminal hairs (large, pigmented hairs) in the pubic and axillary regions in women, as well as the beard area in men.^2,7 Interestingly, the same circulating androgens cause miniaturization of the susceptible hair follicles of the central scalp.⁷ The susceptibility of the hair follicle to the effects of the androgens may be genetically determined.^7,8

Hirsutism is a sign of hyperandrogenism and increased action of androgens on hair follicles. In women, about half of circulating testosterone arises from the ovaries and adrenal glands; the rest originates from peripheral conversion of weaker androgens (such as androstenedione produced by the adrenals and ovaries) into testosterone.⁹ Dehydroepiandrosterone sulfate (DHEAS) originates mainly in the adrenal glands.^9,10 Testosterone is converted to the more potent dihydrotestosterone (DHT) by type II 5-alpha reductase in the skin, which can then act on susceptible hair follicles.^7,11 Therefore, hirsutism can be a consequence of endogenous androgen over-production from the ovaries or the adrenal glands (or both), of exposure to an exogenous source of androgen such as a drug, or of heightened hair follicle sensitivity and metabolism of normal circulating androgen levels (target end-organ dysfunction).¹

‘IDIOPATHIC’ HIRSUTISM: A MISLEADING DIAGNOSIS

Many women with hirsutism are found to have polycystic ovary syndrome as the underlying cause, but hirsutism is also commonly labeled as idiopathic when it occurs without an obvious cause, eg, in women with regular menses and normal androgen levels and without features suspicious for other causes of hirsutism. ^1,2,12,13 But while this term is commonly used,^1,12 it may be misleading, especially if the diagnosis of idiopathic hirsutism is based on standard laboratory tests, which do not always detect androgen excess.^2,13 Minor ovarian or adrenal functional hyperandrogenism,¹⁴ increased peripheral activity of 5-alpha reductase in the hair follicle, or abnormalities in the androgen receptor have been implicated in the pathogenesis of so-called idiopathic hirsutism. ^2,15

HIRSUTISM AND POLYCYSTIC OVARY SYNDROME

Polycystic ovary syndrome, a metabolic syndrome, presents clinically with menstrual irregularities such as oligomenorrhea or amenorrhea, infertility, and signs of hyperandrogenism such as hirsutism, acne, or androgenetic alopecia.^16,17 Metabolic disturbances including insulin resistance, impaired glucose tolerance, hyperlipidemia, and obesity (body mass index > 30 kg/m²) also can occur, thus increasing cardiovascular risk.^16–18

The finding of polycystic ovaries is not required to make the diagnosis of polycystic ovary syndrome, and their presence does not prove the diagnosis.^16,19 Gonadotropin-dependent functional ovarian hyperandrogenism is believed to cause this syndrome; however, mild adrenocorticotropic-dependent functional adrenal hyperandrogenism also is a feature in many cases. In rare cases, polycystic ovary syndrome presents with an isolated elevation of DHEAS.^16,20

OTHER CONDITIONS OF EXCESS ANDROGEN

The syndrome of hyperandrogenism, insulin resistance, and acanthosis nigricans, abbreviated as HAIR-AN, is separate from polycystic ovary syndrome; it characterizes a group of inherited syndromes associated with severe metabolic abnormalities of insulin and glucose metabolism and with marked clinical signs of hyperandrogenism.¹²

The syndrome of seborrhea, acne, hirsutism, and acanthosis nigricans, abbreviated as SAHA, while not itself a diagnosis, is a clinical spectrum of dermatologic signs and symptoms also associated with hyperandrogenism. These are signs that may present with the HAIR-AN syndrome or with another cause of excess androgens, such as idiopathic, ovarian, adrenal, or hyperprolactinemic hyperandrogenism.²¹

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FIGURE 1.

A modification of the Ferriman-Gallwey scoring system. A score of 8 or more indicates hirsutism.

Thyroid disease, hyperprolactinemia, acromegaly, Cushing syndrome, exogenous factors such as androgenic drugs, and nonclassical congenital adrenal hyperplasia can also produce hirsutism.¹² In nonclassical congenital adrenal hyperplasia, which is typically caused by a deficiency of 21-hydroxylase, patients present with premature pubarche, hirsutism in the prepubertal years, and menstrual irregularities including primary amenorrhea.^22,23

Important rare causes of hirsutism include benign and malignant androgen-secreting tumors of adrenal or ovarian origin. In such cases, hirsutism can have an acute onset or rapid progression and may be associated with features of virilization, such as deepened voice, increased muscle mass, androgenetic alopecia, clitoromegaly, and increased libido.¹²

A THOROUGH HISTORY IS CRITICAL TO DIAGNOSIS

A thorough medical history can provide important diagnostic clues in women with hirsutism. The clinician should elicit details about the onset and progression of the hair growth,^12,15 previous treatments, and any cutaneous signs of hyperandrogenism, such as acne, seborrhea, acanthosis nigricans, or patterned hair loss.

Also important are the menstrual history and a history of infertility. Primary amenorrhea is defined as failure to menstruate by 16 years of age if secondary sexual characteristics have developed, or by 14 years of age if no secondary sexual characteristics have developed, and it can indicate nonclassical congenital adrenal hyperplasia.

The clinician should also try to determine if the patient has a history of galactorrhea or symptoms of virilization (eg, deepened voice, clitoromegaly, increased muscle mass); a family history of hirsutism, polycystic ovary syndrome, HAIR-AN syndrome, metabolic conditions such as type 2 diabetes mellitus, or cardiovascular disease^12,15; or a history of symptoms of any condition known to produce hirsutism, such as Cushing disease, acromegaly, or a thyroid disorder. Also important is a drug history to determine if the patient has taken drugs such as androgens, anabolic steroids, or valproic acid (Depakote).²⁰

THE PHYSICAL EXAMINATION

The physical examination involves use of the Ferriman-Gallwey hirsutism scoring system or a modified Ferriman-Gallwey scoring system (FIGURE 1), which helps categorize the severity and distribution of excess hair growth. A Ferriman-Gallwey score of 8 to 15 (out of a possible 36) indicates moderate hirsutism, whereas a score above 15 indicates severe hirsutism.^2,15

Another proposed predictor of hirsutism is that terminal hair on the chin or the lower abdomen (Ferriman-Gallwey score ≥ 2) is nearly 100% sensitive and 27% specific at predicting total-body hirsutism.²⁴

As part of the physical examination, the clinician should also look for other cutaneous signs of hyperandrogenism, such as acne, androgenetic alopecia, and seborrhea. Acanthosis nigricans is a sign of insulin resistance. Height and weight should be measured and the body mass index calculated. Blood pressure should be recorded, as high blood pressure may be seen in Cushing syndrome and is an important cardiovascular risk factor. Signs of virilization should be identified. Indicators of Cushing disease such as striae, moon facies, fat redistribution, fragile skin, and proximal myopathy should be noted as well as signs of thyroid disease, such as textural skin changes, goiter, and hair loss. Expressible or spontaneous galactorrhea suggests hyperprolactinemia. Acromegaly is associated with coarse facies and enlarged hands and feet. Many of the endocrinopathies can be caused by a pituitary adenoma, which can manifest as a visual field defect, so visual fields should be examined.²⁵ The examination should also exclude any palpable ovarian or adrenal mass.¹²

WHEN IS ADDITIONAL TESTING NEEDED?

Laboratory and radiologic testing in patients with hirsutism may be needed to confirm the diagnosis of a suspected underlying condition or to exclude serious underlying pathology (TABLE 1).^{1,12,15–18,20,22,23,25–28}

The current Endocrine Society guidelines²⁰ recommend obtaining an early-morning testosterone blood level in the following patients:

• Women with moderate or severe hirsutism

• Women with hirsutism of any degree with sudden onset or rapid progression, or accompanied by signs or symptoms suggesting malignancy or polycystic ovary syndrome: eg, menstrual irregularity, infertility, central obesity, clitoromegaly, or acanthosis nigricans.^15,20

Testing androgen levels in mild, isolated hirsutism has not been proven to be useful or to alter management.²⁰

Free testosterone level

An early-morning total or free testosterone level is the initial test in the laboratory evaluation of hirsutism.^12,15 Additional specialized laboratory testing may be needed to determine the free testosterone level,¹⁵ as the free testosterone test is not available at all laboratories. A normal total testosterone level does not exclude hyperandrogenism but can suggest the diagnosis of idiopathic hirsutism.¹⁵

Further testing is needed if the total testosterone level is normal or only slightly elevated, or if there is a strong clinical suspicion of an underlying condition such as endocrinopathy or tumor. It is also useful in patients whose hirsutism responds poorly to medical treatments¹⁵ (see discussion below).

If the total testosterone level is elevated, if the hirsutism is moderate to severe, if there are associated symptoms, or if hirsutism is acute or progressive, a further endocrinologic workup is needed,¹⁵ possibly including measurement of free testosterone, sex hormone-binding globulin, DHEAS, and androstenedione.¹⁵ Free testosterone, unbound to sex hormone-binding globulin, is the biologically active fraction, with the levels of binding globulin increased by drugs such as oral contraceptives¹⁵ and decreased by high insulin levels in insulin resistance.²⁵

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TABLE 1

Tests suggested in the workup of hirsutism

Test in patients with mild hirsutism?

Although the guidelines suggest that no additional workup is necessary for women with mild hirsutism, we evaluate all patients with hirsutism and those with the SAHA clinical spectrum by measuring free and total testosterone and DHEAS. In our experience, even women with mild hirsutism with subtle symptoms and signs of hyperandrogenism and mild hirsutism often have elevated androgen levels.

Test in women with idiopathic hirsutism?

In women with idiopathic hirsutism, minor forms of functional ovarian and adrenal hyperandrogenism are believed to play a role and are thought to be undetectable with conventional testing.²⁵ The gonadotropin-releasing hormone (GnRH) analogue stimulation test may uncover occult hyperandrogenism in this setting, but it is used as a research tool and does not currently have application in routine clinical practice.¹⁴

It is important to remember that some women with apparent idiopathic hirsutism and a history of regular menstrual cycles are actually oligo-ovulatory or anovulatory. In these instances, another diagnosis should be considered,¹³ and referral to an endocrinologist for further evaluation of ovulatory function is recommended.¹³

CURRENT USE OF DIAGNOSTIC IMAGING

When malignancy is suspected

A testosterone level above 200 ng/dL suggests an ovarian tumor, and a DHEAS level above 700 μg/dL suggests an adrenal tumor.²⁶ However, not all tumors present with such high androgen levels, and sudden onset of hirsutism, rapid progression of hirsutism, or signs of virilization suggest a tumor.¹⁵ In such cases, transvaginal ultrasonography, computed tomography, or magnetic resonance imaging (MRI) of the abdomen can exclude an ovarian or adrenal tumor.

When polycystic ovary syndrome is suspected

The diagnosis of polycystic ovary syndrome is confirmed by two out of three criteria:

• Oligo-ovulation or anovulation

• Clinical or laboratory signs of hyperandrogenism

• Ultrasonographic evidence of polycystic ovaries, with exclusion of other causes of hyperandrogenism.

ADDITIONAL LABORATORY TESTING

Tests for polycystic ovary syndrome

Assessment of polycystic ovary syndrome involves transvaginal ultrasonography, but ultrasonographic evidence of a polycystic ovary is not necessary for the diagnosis.¹⁶ A fasting lipid profile and fasting serum glucose are recommended, and if the fasting serum glucose is normal, an oral glucose tolerance test is recommended. ¹⁷

Some have reported measuring the ratio of luteinizing hormone to follicle-stimulating hormone in the workup of polycystic ovary syndrome, and a ratio greater than 2 has been considered indicative but not diagnostic.^16,25 The individual levels of luteinizing hormone, follicle-stimulating hormone, and estradiol are more important in the evaluation of infertility and ovulatory dysfunction. In patients with elevations of these hormones or with these symptoms, referral for infertility screening with an endocrinologist or gynecologist is recommended. ²⁵

Additional testing and referral for Cushing syndrome, other conditions

Cushing syndrome can be tested for with a 24-hour urine cortisol, overnight low-dose dexamethasone suppression test, and late-night salivary cortisol.^27,28 Referral to an endocrinologist for further testing can differentiate between corticotropin-dependent or corticotropin-independent Cushing syndrome.²⁵ Cushing syndrome is often associated with hyperandrogenism, particularly in those cases caused by adrenal tumors.²⁹

The prolactin level and the level of somatomedin C (insulin-like growth factor 1) can be used to rule out hyperprolactinemia and acromegaly, respectively.¹² If Cushing syndrome, hyperprolactinemia, or acromegaly is diagnosed by endocrinologic testing, pituitary MRI should be performed.^12,25

Referral to specialist centers with experience with these conditions is essential. Nonclassical congenital adrenal hyperplasia can be screened for by a serum 17-hydroxyprogesterone level measured in the follicular phase.¹² Measurement of thyroid-stimulating hormone, free thyroxine, and thyroid peroxidase antibodies screens for thyroid disease.¹² Hirsutism has been reported with the commencement of L-thyroxine therapy.³⁰

THE PRINCIPLES OF TREATMENT

Patient education regarding the cause of hirsutism and reasonable treatment expectations and emotional support are important in the management of hirsutism. Also important is regular follow-up to measure and document the response to treatment; this can include repeating Ferriman-Gallwey scoring, taking photographs of affected areas, and retesting androgen levels after 3 to 6 months.¹²

Treatment must be continued for an ongoing effect, and most pharmacologic treatments can take up to 3 to 6 months to produce significant improvement.¹

When an underlying condition is diagnosed, treatment of the condition is essential. Androgen-secreting tumors require surgical management.¹² Cushing disease, hyperprolactinemia, and acromegaly should be clinically apparent from examination and testing, and appropriate referral and standard management should be instigated. Exogenous sources of androgen such as androgenic progestins or anabolic steroids should be discontinued. Lifestyle management is important, and weight loss in obese patients with polycystic ovary syndrome can improve hirsutism as well as mitigate cardiovascular risk factors.³¹

In classic congenital adrenal hyperplasia, glucocorticoid therapy manages both ovulation induction and hirsutism.²⁰ However, in nonclassical congenital adrenal hyperplasia, glucocorticoid therapy supports ovulation induction, but hirsutism usually requires both systemic antiandrogen and hair removal.²⁰

CURRENT OPTIONS FOR HAIR REMOVAL

The mainstay of treatment of hirsutism is removing the excess hair. Options (TABLE 2) include inexpensive, home-based, self-care methods such as plucking, shaving, waxing, using depilatory creams, and bleaching, and more expensive clinic-based treatments such as clinic-based waxing, electrolysis, and laser hair removal. These methods can also be combined with drug therapy.¹

The choice of method depends on patient preference, adverse effects, the degree of hirsutism, the level of distress, previous treatments, and cost.^1,15,32

Self-care methods

Self-care methods offer only temporary reduction of excess hairs.

Plucking removes the entire hair, including the root, but it is painful and time-consuming, and it is only practical for areas where few hairs exist, such as on the face.¹

Shaving is an easy, inexpensive, and painless choice for hair removal. Although a common belief is that shaving causes faster or thicker hair regrowth, shaving affects neither the diameter nor the rate of growth of the hair.³² Given its masculine association, shaving is not acceptable to most women except perhaps for use on the legs and axillae.^1,32 Shaving can cause irritation, folliculitis, pseudofolliculitis, and infection.¹

Waxing removes the entire hair. While it is more expensive than plucking, regrowth is slower, occurring over weeks. It is painful and can cause thermal burns, irritation, folliculitis, scarring, and postinflammatory dyspigmentation.¹

Chemical depilatories, usually thioglycollic acid preparations, are inexpensive, painless, and easy to use. However, the resulting hair reduction is of short duration because the hair shafts are only removed at the level of the skin surface.¹ They can also cause irritant dermatitis. ¹

Bleaching with hydrogen peroxide is inexpensive and can camouflage dark facial hair, but it can also cause skin discoloration and irritation. ¹

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TABLE 2

Hair removal methods and their potential side effects

Clinic-based methods

Electrolysis often results in a permanent reduction in hair growth.^1,32 A fine needle is placed into the hair follicle and an electrical current is applied. Each follicle is treated individually. ^1,32 Best results are seen on darker hairs in patients with lighter skin, but it can be used on all skin types and hair colors.^1,32

Electrolysis is operator-dependent, and there are US Food and Drug Administration (FDA) regulations regarding electrolysis techniques. It requires multiple treatments, and it is painful and can cause erythema, folliculitis, pseudofolliculitis, infection, scarring, and postinflammatory dyspigmentation.^1,32 Some reports suggest that prior waxing and plucking of hairs damages the hair by twisting the hair shaft, making electrolysis more difficult.³²

Laser treatment uses light of certain wavelengths to damage the hair follicles. While laser hair removal does not result in complete or persistent hair removal, it is more effective than shaving, waxing, and electrolysis, producing partial hair reduction for up to 6 months; the effect is enhanced with multiple treatments.^33,34 The number of treatments required depends on the laser type and on the nature of the patient’s hair follicles.³⁵

Laser systems for hair removal are of various wavelengths and also include intense pulsed light systems. The choice of system depends on the patient’s skin type and hair color. Women with fair skin and dark hair are ideal candidates; longer-wavelength lasers are preferred for darker or tanned skin types.

Adverse effects of laser hair removal include pain, erythema, burns, dyspigmentation, and scarring. Laser cooling devices can prevent or minimize some of these effects. Laser treatment has also been known to cause a paradoxical increase in hair growth.^1,33,34

DRUG THERAPIES FOR HIRSUTISM

Another option for hair removal in patients with hirsutism is drug therapy (TABLE 3).^{1,12,15,20,31,32,36–42} Several meta-analyses have studied drug treatments for hirsutism and treatment guidelines have been published. ^20,36–38 However, the studies are limited by the heterogeneity of patients with hirsutism, small sample sizes, limited methodology, and failure to distinguish between the types of hirsutism.

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TABLE 3

Possible side effects of drug treatments for hirsutism

The drugs most commonly used for hirsutism are oral contraceptives (off-label use) and antiandrogenic drugs (off-label use). Topical eflornithine cream (Vaniqa) is FDA-approved for hirsutism but is less commonly used. Insulin sensitizers, GnRH analogues, and other drugs are occasionally used (off-label) to treat hirsutism.

Topical eflornithine cream

Topical eflornithine cream treats facial hirsutism by slowing the rate of hair growth; it does this by irreversibly inhibiting ornithine decarboxylase, an enzyme essential for hair growth.^39,40 Studies showed that twice-daily application reduced unwanted facial hair in women after 24 weeks of treatment.^39,40 Treatment must be continuous, since hair growth rapidly returns to the pretreatment rate by 8 weeks after discontinuing eflornithine.^39,40 White women have been shown to respond better than black women.³⁹ Adverse effects include a mild burning sensation, acne, pseudofolliculitis barbae, irritation, and allergic contact dermatitis.^39,40 Improved outcomes have been suggested when eflornithine cream is combined with laser hair removal.⁴¹

Oral contraceptives

Oral contraceptives are commonly used off-label for the management of hirsutism.²⁰ Oral contraceptives suppress the secretion of luteinizing hormone and, hence, the synthesis of ovarian androgen, thereby increasing levels of sex hormone-binding globulin and decreasing free plasma testosterone.^1,20 Adrenal androgen production is also slightly reduced.²⁰

Oral contraceptives usually combine a synthetic estrogen and a progestin. Certain progestins are more androgenic and should be avoided.¹

For treating hirsutism, oral contraceptives should be used that contain low-androgenic progestins such as cyproterone acetate (not available in the United States), drosperinone (eg, in Yasmin), norgestimate (eg, in Ortho Tri-Cyclen), or desogestrel (eg, in Mircette).^1,20

Side effects of oral contraceptives include breast tenderness, gastrointestinal upset, headache, loss of libido, hypertension, and the potential risk of venous thromboembolism.^1,15,32,36

Antiandrogenic drugs

Several antiandrogenic drugs are used off-label to treat hirsutism.

Spironolactone (Aldactone), a competitive inhibitor of the androgen receptor and 5-alpha reductase activity,²⁰ can be effective in the treatment of hirsutism. Monotherapy with spironolactone, without an oral contraceptive or other reliable form of contraception, is not recommended because of the teratogenic potential of all antiandrogens to feminize a developing male fetus.²⁰ Thus, reliable contraception should be used in females of childbearing age when starting antiandrogen therapy.

The dosage of spironolactone for hirsutism is usually 100 mg to 200 mg daily.^1,20 Hyperkalemia, polyuria, postural hypotension, irregular menses, and liver abnormalities are among the possible adverse effects (TABLE 3). Spironolactone was found to be tumorigenic in animal studies, although this has unknown relevance in humans.³⁶

Cyproterone, an antiandrogen not available in the United States,⁴² competitively inhibits the androgen receptor and 5-alpha-reductase activity.^1,20,36 It can be used for only the first 10 days of the menstrual cycle (50-mg or 100-mg dose) with an oral contraceptive pill, or in a low dose in a combined oral contraceptive pill (Diane-35 in Canada and the United Kingdom).¹

Side effects are similar to those of oral contraceptives and include fatigue, mood change, risk of venous thromboembolism, and decreased libido.^1,15,36 Importantly, in woman of childbearing age, there is the potential risk of feminization of a male fetus, so reliable contraception must be used.^15,36

Flutamide, an investigational antiandrogen, has shown promise in the treatment of hirsutism.²⁰ Flutamide is a nonsteroidal competitive inhibitor of androgen receptor binding. It carries a significant risk of hepatotoxicity. ^1,15

Finasteride (Propecia) 1 mg is only occasionally used in the treatment of hirsutism (off-label usage). It inhibits type II 5-alphareductase to suppress dihydrotestosterone levels. ³² It carries a risk of gastrointestinal disturbance, decreased libido, hepatotoxicity, and feminization of a male fetus (pregnancy category X), so reliable contraception is required in all females of childbearing age, as with all antiandrogens¹ (TABLE 3).

Dutasteride (Avodart), a type I and II 5-alpha-reductase inhibitor, has not been studied for the treatment of hirsutism (pregnancy category X).

Insulin sensitizers

Metformin (Glucophage) and other insulin sensitizers are less effective than antiandrogens at reducing hirsutism.^20,38 However, metformin is effective at inducing ovulation in patients with polycystic ovary syndrome.³⁸ Gastrointestinal upset is a common side effect; lactic acidosis is a serious but rare adverse effect.¹

Gonadotropin-releasing hormone analogues

GnRH analogues are an option only if oral contraceptives and antiandrogen drugs are unsuccessful in patients with severe hyperandrogenism. ²⁰ They suppress secretion of luteinizing hormone and the synthesis of ovarian androgen.^1,20 These drugs are given as monthly intramuscular injections, usually with some form of estrogen-progestin replacement, since GnRH analogues cause estrogen levels to fall to menopausal levels.¹

Side effects include signs and symptoms of menopause including hot flushes, atrophic vaginitis, and osteoporosis.^1,15 These drugs completely inhibit ovulation, and some endocrinologists and gynecologists do not suggest further contraception in women of childbearing years for this reason. However, GnRH analogues are not approved as a contraceptive and are pregnancy category X.

Other drugs

Other drugs with antiandrogen activity include cimetidine and ketoconazole.¹² Cimetidine (Tagamet) is not effective for the treatment of hirsutism, and ketoconazole (Nizoral) is associated with significant risk for adrenocortical suppression¹² and hepatotoxicity in addition to multiple drug interactions, given its effect on the hepatic P450 enzyme system.

Acknowledgments

Many thanks to Rebecca Tung, MD, dermatologic surgeon, Cleveland Clinic, for her advice on lasers.

• Copyright© 2010 The Cleveland Clinic Foundation

REFERENCES

1. 1.↵
   1. Mofid A,
   2. Seyyed Alinaghi SA,
   3. Zandieh S,
   4. Yazdani T
   . Hirsutism. Int J Clin Pract 2008; 62:433–443.

   CrossRefMedlineWeb of Science

2. 2.↵
   1. Azziz R,
   2. Carmina E,
   3. Sawaya ME
   . Idiopathic hirsutism. Endocr Rev 2000; 21:347–362.

   Abstract/FREE Full Text

3. 3.↵
   1. Himelein MJ,
   2. Thatcher SS
   . Polycystic ovary syndrome and mental health: a review. Obstet Gynecol Surv 2006; 61:723–732.

   CrossRefMedlineWeb of Science

4. 4.↵
   1. Williamson K,
   2. Gunn AJ,
   3. Johnson N,
   4. Milsom SR
   . The impact of ethnicity on the presentation of polycystic ovarian syndrome. Aust N Z J Obstet Gynaecol 2001; 41:202–206.

   MedlineWeb of Science

5. 5.↵
   1. Diamanti-Kandarakis E,
   2. Kouli CR,
   3. Bergiele AT,
   4. et al.
   A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 1999; 84:4006–4011.

   Abstract/FREE Full Text

6. 6.↵
   1. Ferriman D,
   2. Gallwey JD
   . Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961; 21:1440–1447.

   Abstract/FREE Full Text

7. 7.↵
   1. Messenger AG
   . The control of hair growth: an overview. J Invest Dermatol 1993; 101(suppl 1):4S–9S.

   CrossRefMedline

8. 8.↵
   1. Rosenfield RL
   . Hirsutism and the variable response of the pilosebaceous unit to androgen. J Investig Dermatol Symp Proc 2005; 10:205–208.

   CrossRefMedline

9. 9.↵
   1. Longcope C
   . Adrenal and gonadal androgen secretion in normal females. Clin Endocrinol Metab 1986; 15:213–228.

   CrossRefMedlineWeb of Science

10. 10.↵
    1. Gardner DG,
    2. Shoback D
    1. Braunstein GD
    . Testis. In: Gardner DG, Shoback D, editors. Greenspan’s Basic & Clinical Endocrinology. 8th ed. New York: McGraw-Hill, 2007.
11. 11.↵
    1. Deplewski D,
    2. Rosenfield RL
    . Role of hormones in pilosebaceous unit development. Endocr Rev 2000; 21:363–392.

    Abstract/FREE Full Text

12. 12.↵
    1. Practice Committee of the American Society for Reproductive Medicine
    . The evaluation and treatment of androgen excess. Fertil Steril 2006; 86(suppl 5):S241–S247.

    Medline

13. 13.↵
    1. Azziz R,
    2. Waggoner WT,
    3. Ochoa T,
    4. Knochenhauer ES,
    5. Boots LR
    . Idiopathic hirsutism: an uncommon cause of hirsutism in Alabama. Fertil Steril 1998; 70:274–278.

    CrossRefMedline

14. 14.↵
    1. Rossi R,
    2. Tauchmanovà L,
    3. Luciano A,
    4. et al.
    Functional hyperandrogenism detected by corticotropin and GnRH-analogue stimulation tests in women affected by apparently idiopathic hirsutism. J Endocrinol Invest 2001; 24:491–498.

    Medline

15. 15.↵
    1. Rosenfield RL
    . Clinical practice. Hirsutism. N Engl J Med 2005; 353:2578–2588.

    FREE Full Text

16. 16.↵
    1. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group
    . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19:41–47.

    Abstract/FREE Full Text

17. 17.↵
    1. Salley KE,
    2. Wickham EP,
    3. Cheang KI,
    4. Essah PA,
    5. Karjane NW,
    6. Nestler JE
    . Glucose intolerance in polycystic ovary syndrome—a position statement of the Androgen Excess Society. J Clin Endocrinol Metab 2007; 92:4546–4556.

    Abstract/FREE Full Text

18. 18.↵
    1. Eckel RH,
    2. Grundy SM,
    3. Zimmet PZ
    . The metabolic syndrome. Lancet 2005; 365:1415–1428.

    CrossRefMedlineWeb of Science

19. 19.↵
    1. Azziz R
    . Diagnostic criteria for polycystic ovary syndrome: a reappraisal. Fertil Steril 2005; 83:1343–1346.

    CrossRefMedlineWeb of Science

20. 20.↵
    1. Martin KA,
    2. Chang RJ,
    3. Ehrmann DA,
    4. et al.
    Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. http://www.endo-society.org/guidelines/final/upload/Hirsutism_Guideline.pdf. Accessed March 30, 2010.
21. 21.↵
    1. Orfanos CE,
    2. Adler YD,
    3. Zouboulis CC
    . The SAHA syndrome. Horm Res 2000; 54:251–258.

    CrossRefMedline

22. 22.↵
    1. New MI
    . Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 2006; 91:4205–4214.

    Abstract/FREE Full Text

23. 23.↵
    1. Kohn B,
    2. Levine LS,
    3. Pollack MS,
    4. et al.
    Late-onset steroid 21-hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 1982; 55:817–827.

    Abstract/FREE Full Text

24. 24.↵
    1. Knochenhauer ES,
    2. Hines G,
    3. Conway-Myers BA,
    4. Azziz R
    . Examination of the chin or lower abdomen only for the prediction of hirsutism. Fertil Steril 2000; 74:980–983.

    CrossRefMedlineWeb of Science

25. 25.↵
    1. Somani N,
    2. Harrison S,
    3. Bergfeld WF
    . The clinical evaluation of hirsutism. Dermatol Ther 2008; 21:376–391.

    CrossRefMedline

26. 26.↵
    1. Waggoner W,
    2. Boots LR,
    3. Azziz R
    . Total testosterone and DHEAS levels as predictors of androgen-secreting neoplasms: a populational study. Gynecol Endocrinol 1999; 13:394–400.

    MedlineWeb of Science

27. 27.↵
    1. Crapo L
    . Cushing’s syndrome: a review of diagnostic tests. Metabolism 1979; 28:955–977.

    CrossRefMedlineWeb of Science

28. 28.↵
    1. Blethen SL,
    2. Chasalow FI
    . Overnight dexamethasone suppression test: normal responses and the diagnosis of Cushing’s syndrome. Steroids 1989; 54:185–193.

    CrossRefMedline

29. 29.↵
    1. Bertagna C,
    2. Orth DN
    . Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 1981; 71:855–875.

    CrossRefMedlineWeb of Science

30. 30.↵
    1. Kologlu S,
    2. Baskal N,
    3. Kologlu LB,
    4. Laleli Y,
    5. Tuccar E
    . Hirsutism due to the treatment with L-thyroxine in patients with thyroid pathology. Endocrinologie 1988; 26:179–185.

    Medline

31. 31.↵
    1. Gambineri A,
    2. Patton L,
    3. Vaccina A,
    4. et al.
    Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: a randomized, 12-month, placebo-controlled study. J Clin Endocrinol Metab 2006; 91:3970–3980.

    Abstract/FREE Full Text

32. 32.↵
    1. Dawber RP
    . Guidance for the management of hirsutism. Curr Med Res Opin 2005; 21:1227–1234.

    CrossRefMedline

33. 33.↵
    1. Haedersdal M,
    2. Wulf HC
    . Evidence based review of hair removal using lasers and light sources. J Eur Acad Dermatol Venereol 2006; 20:9–20.

    CrossRefMedlineWeb of Science

34. 34.↵
    1. Sadighha A,
    2. Mohaghegh Zahed G
    . Meta-analysis of hair removal laser trials. Lasers Med Sci 2009; 24:21–25.

    CrossRefMedline

35. 35.↵
    1. Casey AS,
    2. Goldberg D
    . Guidelines for laser hair removal. J Cosmet Laser Ther 2008; 10:24–33.

    CrossRefMedline

36. 36.↵
    1. Wakelin SH,
    2. Maibach HI
    , editors. Handbook of Systemic Drug Treatment in Dermatology. London: Manson Publishing Ltd, 2004.
37. 37.
    1. Swiglo BA,
    2. Cosma M,
    3. Flynn DN,
    4. et al.
    Clinical review: antiandrogens for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab 2008; 93:1153–1160.

    Abstract/FREE Full Text

38. 38.↵
    1. Cosma M,
    2. Swiglo BA,
    3. Flynn DN,
    4. et al.
    Clinical review: insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab 2008; 93:1135–1142.

    Abstract/FREE Full Text

39. 39.↵
    1. Balfour JA,
    2. McClellan K
    . Topical eflornithine. Am J Clin Dermatol 2001; 2:197–201.

    CrossRefMedline

40. 40.↵
    1. Wolf JE Jr,
    2. Shander D,
    3. Huber F,
    4. et al.,
    5. Eflornithine HCl Study Group
    . Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCl 13.9% cream in the treatment of women with facial hair. Int J Dematol 2007; 46:94–98.
41. 41.↵
    1. Hamzavi I,
    2. Tan E,
    3. Shapiro J,
    4. Lui H
    . A randomized bilateral vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women. J Am Acad Dermatol 2007; 57:54–59.

    CrossRefMedline

42. 42.↵
    1. Van der Spuy ZM,
    2. le Roux PA
    . Cyproterone acetate for hirsutism. Cochrane Database Syst Rev 2003; 4:CD001125.

    Medline

From http://www.ccjm.org/content/77/6/388.full

Hydrocortisone Dosing during Puberty in Patients with Classical Congenital Adrenal Hyperplasia: An Evidence-Based Recommendation

Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2009-0942
The Journal of Clinical Endocrinology & Metabolism Vol. 94, No. 10 3882-3888
Copyright © 2009 by The Endocrine Society

Hydrocortisone Dosing during Puberty in Patients with Classical Congenital Adrenal Hyperplasia: An Evidence-Based Recommendation

Walter Bonfig, Susanne Bechtold Dalla Pozza, Heinrich Schmidt, Philipp Pagel, Dietrich Knorr and Hans Peter Schwarz

University Children’s Hospital (W.B., S.B.D.P., H.S., D.K., H.P.S.), Ludwig Maximilians University, Division of Pediatric Endocrinology, D-80337 Munich, Germany; and Division of Bioinformatics (P.P.), Technical University, D-80337 Munich, Germany

Address all correspondence and requests for reprints to: Walter Bonfig, M.D., University Children’s Hospital, Division of Endocrinology, Ludwig Maximilians University, Lindwurmstr. 4, D-80337 Munich, Germany. E-mail: walter.bonfig@med.uni-muenchen.de.

Context: Patients with congenital adrenal hyperplasia (CAH) are at risk for early pubertal development and diminished pubertal growth. Liberal treatment with glucocorticoids will prevent early puberty but may inhibit growth outright.

Objective: The aim of the study was to determine an optimal range for hydrocortisone dosing during puberty in children with classical CAH who were exclusively treated with hydrocortisone.

Methods: The effects of glucocorticoid treatment for classical CAH were retrospectively analyzed in 92 patients (57 females). Growth pattern, final height (FH), and mean daily hydrocortisone dose were recorded.

Results: Pubertal growth was significantly reduced in all patients: salt-wasting (SW) females, 13.8 ± 7.4 cm; simple virilizing (SV) females, 13.1 ± 6.2 cm; vs. reference, 20.3 ± 6.8 cm (P < 0.05); and SW males, 17.7 ± 6.7 cm; SV males, 16.2 ± 5.7 cm; vs. reference, 28.2 ± 8.2 cm (P < 0.05). Decreased pubertal growth resulted in FH at the lower limit of genetic potential (corrected FH in SW females, –0.6 ± 0.9; SV females, –0.3 ± 0.9; SW males, –0.8 ± 0.8; and SV males, –1.0 ± 1.0). During puberty, mean daily hydrocortisone dose was 17.2 ± 3.4 mg/m2 in females (SW, 17.0 ± 3.3; SV, 17.4 ± 3.5) and 17.9 ± 2.5 mg/m2 in males (SW, 17.4 ± 2.0; SV, 18.7 ± 3.1). In a logistic regression model, a significant correlation between hydrocortisone dose and FH was found (P < 0.01), and the positive predictive value for short stature rose from below 30% to above 60% when hydrocortisone dose exceeded 17 mg/m2.

Conclusion: With conventional hydrocortisone treatment, pubertal growth is significantly reduced in both sexes, resulting in a FH at the lower limit of genetic potential. These deleterious effects on pubertal growth can be reduced if hydrocortisone does not exceed 17 mg/m2.

From http://jcem.endojournals.org/cgi/content/abstract/94/10/3882

Gender Role Behavior, Sexuality, and Psychosocial Adaptation in Women with Congenital Adrenal Hyperplasia due to CYP21A2 Deficiency

Louise Frisén, Anna Nordenström, Henrik Falhammar, Helena Filipsson, Gundela Holmdahl, Per Olof Janson, Marja Thorén, Kerstin Hagenfeldt, Anders Möller and Agneta Nordenskjöld1

Department of Psychiatry (L.F.), Danderyd Hospital, SE-18287 Stockholm, Sweden; Department of Clinical Sciences (L.F.), Karolinska Institutet, Danderyd Hospital, SE-171 77 Stockholm, Sweden; Department of Pediatrics (An.N.), Astrid Lindgren Children Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Clinical Science, Intervention, and Technology (An.N.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Endocrinology, Metabolism and Diabetes (H.Fa., M.T.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery (H.Fa., M.T.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Endocrinology (H.Fi.), Sahlgrenska University Hospital, Sahlgrenska Academy at University of Gothenburg, S-405 30 Gothenburg, Sweden; Department of Pediatric Surgery (G.H.), Queen Silvia Children Hospital, Sahlgrenska Academy at University of Gothenburg, S-405 30 Gothenburg, Sweden; Department of Obstetrics and Gynecology (P.O.J.), Sahlgrenska University Hospital, Sahlgrenska Academy at University of Gothenburg, S-405 30 Gothenburg, Sweden; Department of Woman and Child Health (K.H., Ag.N.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Nordic School of Public Health (A.M.), SE-402 42 Gothenburg, Sweden; and Department of Pediatric Surgery (Ag.N.), Astrid Lindgren Children Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden

Address all correspondence and requests for reprints to: Louise Frisén, M.D., Ph.D., Research and Development Section, Department of Psychiatry, Danderyd Hospital, SE-18287 Danderyd, Sweden. E-mail: louise.frisen@ki.se.

Context: Gender-atypical behavior has been described in young girls as well as in women with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency.

Objective: The aim of the study was to assess health-related, psychosexual, and psychosocial parameters and correlate the results to CYP21A2 genotype.

Design and Participants: Sixty-two Swedish women with CAH and age-matched controls completed a 120-item questionnaire and a validated quality of life instrument [psychological general well-being (PGWB) formula] to identify psychosexual and psychosocial parameters. The patients were divided into four CYP21A2 genotype groups.

Results: The women with CAH held more male-dominant occupations (30%) compared to controls (13%) (P = 0.04), especially those in the null genotype group (55%) (P = 0.006). They also reported a greater interest in rough sports (74%) compared to controls (50%) (P = 0.007). Eight women with CAH (14%) reported a prime interest in motor vehicles, compared to none of the controls (P = 0.002). Non-heterosexual orientation was reported by 19% of women with CAH (P = 0.005), 50% in the null genotype group (P = 0.0001), 30% in I2splice (NS), and 5% in I172N (NS). PGWB total score did not differ between patients and controls.

Conclusion: We identified increased gender-atypical behavior in women with CAH that could be correlated to the CYP21A2 genotype. This speaks in favor of dose-dependent effects of prenatal androgens on the development of higher brain functions. The impact of the disease on upbringing and interpersonal relationships did not correlate with disease severity, indicating that other factors, such as coping strategies, are important for psychosocial adaptation. This illustrates the need for psychological support to parents and patients.

from http://jcem.endojournals.org/cgi/content/abstract/94/9/3432