Fifteen-year-old Janice was becoming increasingly depressed by the constant teasing of her female friends. Breast development started normally at age eleven, followed by menarche (first menstrual period) at age twelve and a half. Now, three years later, Janice had experienced only three additional menstrual periods. This concerned her because her friends were all “regular” with their menstrual cycles. She had annoying outbreaks of acne, and her skin was very oily. When she was thirteen, her mother took her to their family physician concerned about irregular periods. At that time, the physician explained that menstrual cycles often take a long time to regulate. He also explained that acne and some facial hair were not unusual during early adolescence and tended to decrease with time. Currently, Janice’s major complaint was how hairy she had become. She had noticeable coarse dark hair above her upper lip, on her chin, and around her nipples. She would not wear a two-piece bathing suit at the beach because she had a streak of dark hair running from her pubis up the center of her abdomen. Her thighs and lower back also grew dark hair. Her friends who had seen her undressed said she had hair “like a boy,” and the teasing increased. She also began to put on weight. Janice visited her physician again. The physician carefully examined Janice and confirmed that she had an unusual amount of hair that was distributed in a male pattern (hirsutism). Janice had persistent oligomenorrhea (few menstrual periods) and had remained amenorrheic for over three months. The physician was also concerned about Janice’s weight gain and referred her to a gynecologist who specialized in endocrine and developmental problems. The gynecologist confirmed a diagnosis of hirsutism. This finding, along with acne, prolonged amenorrhea, and increasing weight gain, suggested that Janice was suffering from an excess of androgens (male hormones), which could be responsible for her symptoms. A very common endocrine disorder, polycystic ovary syndrome (PCOS), occurs in up to 10 percent of females and is associated with hyperandrogenism. PCOS is often diagnosed during adolescence. The gynecologist ordered a series of additional tests for Janice to rule out other possible causes of hyperandrogenism. These included determination of blood testosterone levels (and a number of other endocrine hormone level determinations), ovarian ultrasound, insulin levels, and glucose tolerance testing. Test results disclosed an abnormally high androgen levels without an indication of adrenal or thyroid dysfunction. Janice had high levels of circulating insulin and an abnormal glucose tolerance test, suggesting the early onset of insulin resistance. Abdominal ultrasound suggested increased ovarian volume (but this is a common finding in adolescents). Janice underwent transvaginal ultrasound and was found to have an excess of cystic areas on her ovaries, consistent with PCOS. Janet’s gynecologist diagnosed PCOS based on the findings of hyperandrogenism and ovulatory dysfunction (in the absence of other factors), polycystic ovaries, and the suggestion of early onset type 2 diabetes with obesity. Janice was treated with combination birth control pills (containing both estrogen and progesterone) and an androgen blocking agent (spironolactone). This regularized her menses and reduced the hirsutism. She was counseled regarding a healthy lifestyle, including exercise and weight control. The drug metformin was also prescribed because of increasing concern about her diabetes.
Discussion
One might imagine that PCOS would be relatively easy to diagnose in an adolescent considering the distinctive signs and symptoms. This is incorrect. Normal body hair distribution varies greatly from person to person, dependent upon both degree of sexual development and, in particular, ethnic origin. For example, what might be considered as an abnormal amount of hair in a person of Chinese (Han) origin might be quite normal in a white or black female.
The semiquantitative Ferriman-Gallwey score can be used in the clinical assessment of hair, but half of women with isolated hirsutism are found not to have excess androgens. For this reason, only moderate to extreme excess of hair (particularly in a male growth pattern) is suggestive of PCOS. Laboratory testing for levels of circulating androgens (testosterone) is difficult to perform and interpret. There is no universally accepted “normal” level, particularly in developing female adolescents. Another complicating factor is that much of the testosterone in circulation is bound to steroid, hormone-binding globulin and thus is not hormonally active. Hence, determination of androgen level must be done by a reliable laboratory that has established accurate and appropriate normal controls for both sexes at different ages. In the absence of other symptoms, a single high androgen level should be interpreted with caution. In addition, abnormally high androgen levels in a female can be caused by ovarian and adrenal tumors and adrenal hyperplasia. Primary ovarian failure (not related to excess androgen levels) can result from a variety other hormonal abnormalities. Determining whether the ovaries show a polycystic morphology is most commonly accomplished using transvaginal ultrasound, but there is no widely accepted definition for an “abnormal” polycystic ovarian morphology in adolescents. A large number of adolescent females without hyperandrogenism show evidence of such an ovarian morphology. It is accepted that there is a high level of insulin resistance and obesity associated with PCOS in adolescents. Hence, the diagnosis of PCOS requires multifactorial evaluation coupled with clinical expertise to avoid errors in diagnosis. The etiology of PCOS remains uncertain. Clearly, abnormally high androgen levels, produced in the ovary and adrenals, are central in pathogenesis. There is a clear genetic component to PCOS and suggestions of association with a variety of genes in the population. The relation of high insulin level, insulin resistance, and obesity to hyperandrogenism remains speculative but clearly contributes to the hormonal abnormality. To date, the exact cause-effect relationship between PCOS and the associated metabolic disturbances is undefined.
Etiology and Pathogenesis
Polycystic ovary syndrome and associated insulin resistance and obesity resulting in hyperandrogenism and hyperandrogen induced ovarian disease.
Questions
1. What are the milestones in the development of sexual maturity in the female; at what age are they expected to occur?
2. How much variation is considered normal in the menstrual cycle at the start of menarche? after five years?
3. How might a clinician distinguish hyperandrogenism resulting from PCOS from that resulting from other causes (such as a tumor)?
4. What are the differences in distribution of body hair in a normal male and female?