Steroidogenesis pathway.
Adrenal androgen production is controlled by adrenocorticotropic hormone (ACTH). As just described, the main androgen produced is DHEA, and its final active form is DHEAS. With hyperandrogenism, enzyme deficiencies in the androgen production and metabolism pathway lead to precursor molecules such as DHEA and DHEAS accumulation, which can be measured to determine the origin of the hyperandrogenism. DHEA can further be metabolized to androstenedione and testosterone.
Ovarian androgen production (mainly testosterone and some androstenedione) is stimulated by luteinizing hormone (LH) secretion from the pituitary gland. Extraglandular testosterone production occurs in adipocytes and depends on the magnitude of adrenal and ovarian androstenedione production. Obesity increases the conversion of androstenedione to testosterone.
Scope of the problem
Hyperandrogenism, given the variety of etiologies associated with increased androgens in blood, has a significant impact on the population. The number of patients affected by this condition reaches significance secondary to varying causes such as androgen producing tumors, PCOS, to neonatal deficiencies in enzymes such as in congenital adrenal hyperplasia (CAH), the number of patients affected by this condition reaches significance. Many, if not most of the patients with clinical manifestations of increased androgens, seek treatment. Treatment of unwanted hair (hirsutism), acne, and clitoromegaly become as important as treating the original condition. The effects on body image and self-esteem are an integral part of the management of these conditions.
History
As described earlier, hyperandrogenism will present generally one of two ways. Patients may present with hirsutism, alopecia, and acne. They may also present with full virilization signs that include the preceding findings, as well as deepening of the voice, clitoromegaly, and changes in muscle mass distribution. Because of the disruption in ovulation created by high androgen levels, most of these patients will also have some type of menstrual dysfunction including amenorrhea, oligomenorrhea, or irregular menses.
Family history and ethnicity are important factors to consider in these patients. Individuals of Mediterranean ancestry have an increase in concentration of hair follicles, compared to their northern European counterparts. And those of Asian descent have less concentration of hair follicles, and thus are less likely to manifest complaints of hirsutism. These differences can account for the normal variation between ethnicities and do not necessarily signify hyperandrogenism. There are also genetic differences in the sensitivity of follicles to DHT and 5α-reductase that are not necessarily pathologic, and symptomatic patients can display normal androgen levels.[5]
Rapid progression of symptoms is generally indicative of a hormone-producing tumor, either ovarian or adrenal. Symptoms such as abdominal pain, bloating, and back pain could be present. However, most patients with these tumors do not have such symptoms; indeed these tumors are typically diagnosed because the systemic effects of the hormone initiated an evaluation before tumor size contributed to patient complaints.
Some conditions that cause hyperandrogenism can have severe metabolic effects; for example, newborn hypotension is associated with CAH. These conditions can also affect sexual development. Babies with CAH and male pseudohermaphroditism will typically be born with ambiguous genitalia. Teens with male pseudohermaphroditism will often present with virilization symptoms during puberty.
Personal history of hypothyroidism or symptoms such as weight gain, hair loss, central obesity, and anovulation are symptoms of hypothyroidism. If hypothyroidism is confirmed, this diagnosis may be the cause for increased hair growth. Galactorrhea, as a sign of elevated prolactin, has also been associated with hyperandrogenism via an increase in the secretion of adrenal androgens secondary to the stimulation of prolactin receptors in the adrenal gland. Moon facies, abdominal striae, central fat distribution, proximal muscle weakness, and easy bruising are associated with Cushing’s syndrome and should raise suspicion for this condition.
Medication history is important, as some drugs have been identified as contributors to hirsutism even though they may not necessarily cause elevated circulating androgens, but rather have a direct effect on testosterone receptors. These drugs include phenytoin, corticosteroids, danazol, diazoxide, minoxidil, anabolic steroids, and androgens (used by some athletes).[2] Conditions that increase the secretion of LH by the pituitary gland, such as stress, can also lead to an increase in androgen production from the ovarian theca cells and lead to hyperandrogenism and its manifestations.[3]
Physical exam
In this section the different clinical findings associated with elevated androgen will be defined and their clinical assessment will be described.
Hirsutism
Hirsutism is defined as coarse, dark hair distributed in a male pattern. This is different than hypertrichosis, which is lanugo-type hair rather than terminal hair, which is associated with some malignancies and certain medications. The Ferriman-Gallwey scoring system was created as a tool to objectively quantify the degree of hirsutism. This tool has been widely used in research to standardize results on studies, but it is not used commonly in the clinical setting because of its complexity and length. Modified versions have been used in the clinical setting, but most practitioners use a mild, moderate, and severe scale to describe the amount of hair present (Figure 29-2).[6] When evaluating patients for hirsutism, it is important to ask the patients about their hair management habits such as frequency of shaving, plucking, and use of depilatory creams. This information is important because the degree of hirsutism may not be easily appreciated if these techniques are routinely used.
The Ferriman-Gallwey scoring system (with permission from Lara-Torre E, Hertweck PS. Medical management of gynecological problems in the pediatric and adolescent patient. In: Bieber EJ, Sanfilippo JS, Horowitz IR, Shafi MI (eds.). Clinical Gynecology, 2nd edition. Philadelphia: Cambridge Press 2015; figure 36.11, pp 515).
Acne
Acne is caused by an increase in sebaceous gland activity leading to inflammation. The most common areas affected are the face, upper back, and upper torso. An increase in circulating androgens leads to the increased conversion of testosterone to its active metabolite DHT and in turn stimulates the receptors to produce sebum. Long-standing inflammation leads comedone formation, infection with bacteria such as Propionibacterium acnes, and if untreated, could lead to scarring. Most patients can be classified into mild, moderate, or severe depending on the extent of the lesions and the amount of inflammation, comedone formation, and scarring present.[7]
Alopecia
Alopecia is defined as changes in the nonandrogen-dependent hair that lead to balding or thinning of the hair follicles. Patients generally present with thinner or absent scalp hair especially in the crown area, while their frontal hair line is preserved.[8] The degree of alopecia may not necessarily correlate with the levels of androgen in blood.
Clitoromegaly
The normal size of the clitoris has previously been defined as a width of <5 mm, with most normal adult females having a width somewhere between 2 mm and 4 mm in the non-erect state. Patients with a width of 10 mm or greater are considered to have significant virilization. Normal length of the clitoris is 16 mm ±4.3 mm (including glans and body). The normal clitoral index of 18.5 mm2 (product of the glans width times the glans length) has also been reported.[9]
Other signs of virilization can be seen in patients with a significant increase in the amount of active circulating androgens. These include changes in muscle mass distribution, from a female to a male pattern, resulting in an increase in total muscle mass and a broadening of the shoulders. A deepening of the voice and decrease in breast size may also be noted.
Some other physical findings would be dependent on the underlying cause for the increase in androgens. For example, a pelvic mass would be found in patients with an androgen producing ovarian tumor or galactorrhea may be noted on breast exam in those with hyperprolactinemia. Changes associated with Cushing’s and CAH were previously described.
Laboratory analysis
The initial laboratory evaluation of patients should include a baseline assessment of testosterone (free or total), DHEAS, and thyroid-stimulating hormone (TSH), given some of the symptoms of hypothyroidsm are subtle and similar to those of hyperandrogenism. In patients who also present with menstrual irregularities such as oligomenorrhea, adding prolactin, follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) is of value to identify other less common causes such as intersex disorders and prolactinomas, and to rule out pregnancy. Patients with abnormal values in these tests should be managed accordingly; the specific management for each disorder is beyond the scope of this chapter.
The routine measurement of 17-OH progesterone (17-OHP) is not done in every setting, and should only be collected if other signs of virilization are also present or the screening DHEAS is elevated. Measurement of androstenedione may also be indicated in patients with elevation of total testosterone or DHEAS or if there is suspicion for a tumor.
Once the initial results are obtained, these will dictate further steps that need to be undertaken (Figure 29-3). Normal values of all androgens can be seen in some patients with hirsutism. This is referred to as idiopathic hirsutism and is the second most common cause. Total testosterone values over 200 ng/dL, DHEAS values higher than 600 μg/dL–700 μg/dL, or androstenedione of 500 ng/dL are associated with tumors.[10] Imaging of the ovaries with ultrasound (elevated testosterone) and/or adrenal glands with CT/MRI (elevated DHEAS, androstenedione) is indicated. Levels of androgens that fall above the normal range but below the levels just mentioned are unlikely to be associated with tumors, so imaging may not be of benefit. Most of these patients will be ultimately diagnosed with PCOS (see Chapter 28).
Diagnostic algorithm for patients with hirsutism. Patients who underwent 17-OHP testing with results below 200 ng/dL are unlikely to have CAH and require no further testing.[11] If the levels are above 1,000 ng/dL, then the diagnosis of 21-hydroxylase deficiency can be made. If the levels are between 200 ng/dL and 1,000 ng/dL, an ACTH stimulation test is needed to confirm the diagnosis. Patients with clinical manifestations of Cushing’s as described in the chapter should undergo a 24-hour urine free cortisone and creatinine determination followed by a dexamethasone suppression test.[12]
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