Emily Winterton, MD; Kathleen Eyster, PhD; Keith A Hansen M.D.©
Sanford Health Fertility and Reproductive Medicine
1500 W. 22nd Street, Suite 102
Sioux Falls, SD 57105
Hirsutism is a common problem affecting women that is usually the result of a benign etiology. However, sudden onset or rapidly progressive hirsutism, especially when accompanied by virilizing signs, is suspicious for androgen producing neoplasms of the ovaries or adrenals. A 28-year-old female presented with the rapid onset of hirsutism and virilizing signs, accompanied by a markedly elevated serum testosterone. Initial imaging studies demonstrated
normal adrenal glands and ovaries. She was later discovered to have a rare steroid-secreting ovarian tumor. This case emphasizes the importance of a high level of suspicion for an androgen-producing neoplasm in the patient with sudden onset or rapid progression of virilizing signs and symptoms.
Hirsutism is characterized by male-pattern terminal hair growth on the face, chest, upper abdomen, lower back and/or inner thighs. It is a common problem affecting up to 8 percent of adult women.1 Hirsutism is due to increased androgen production or increased sensitivity of the hair follicles to androgens. Hirsutism is usually the result of a benign condition. However, it can be a sign of significant disease especially when sudden in onset or rapidly progressive, and it calls for prompt evaluation.
Virilization in the female is the result of marked elevations in serum androgens. Virilization is characterized by continued and increased male pattern hair growth, male pattern alopecia, increased muscle mass, deepening of the voice, decreased breast size, increased libido, menometrorrhagia or amenorrhea and clitoromegaly. The presence of virilization alerts the health care provider to markedly elevated androgen levels.2
A case of a 28-year-old female with the sudden onset of hirsutism and with rapid progression to virilizing signs accompanied by a markedly elevated testosterone level as the result of an ovarian, androgen-producing tumor is presented.
A 28-year-old female, gravida 11, para 3-0-8-3, was referred for a five-month history of increased male-pattern hair growth, secondary amenorrhea for almost three years, a markedly elevated testosterone and otherwise normal endocrine evaluation. The androgen-dependent hair growth was increasing in severity and primarily located on her face and midline of the abdomen. In addition, she noted accelerated loss of scalp hair in a male pattern.
The patient’s last menstrual period was approximately three years prior to presentation and before the birth of her last child. Menarche occurred at age 14, and her menstrual cycles were always irregular. The patient notes that she has always had a small amount of hair growth on her upper lip, but over the preceding five months there had been a significant increase in hair growth on her face and midline of the abdomen. Over this same time period, she also noted a 30-pound weight gain, increased acne, poor sleep and easy bruising. Spironolactone had been prescribed as treatment for hirsutism as well as metformin for the metabolic syndrome.
Prior laboratory evaluation included normal chemistry panel and complete blood count. She had a negative pregnancy test, normal ACTH, cortisol levels and dexamethasone suppression test. Her fasting glucose was 106 mg/dL and fasting insulin was high at 35 uIU/mL (3-19 uIU/mL). She also had a normal TSH, 17-hydroxyprogesterone, prolactin, FSH, LH, estradiol, aldosterone, renin, and DHEA-S levels. Testosterone was high at 238 ng/dL(15 – 70 ng/dL). Prior imaging included transvaginal ultrasound showing no uterine or ovarian pathology, CT with contrast that showed normal adrenals, and MRI of the sella turcica revealed a normal pituitary.
Physical examination revealed an obese female (BMI 39.5) with normal vital signs. She had moon facies with increased supraclavicular fat pads. She had dark coarse hairs encompassing the whole lower face down onto the neck, diffuse hairs present in the midline of the chest and abdomen, and striae on her abdomen and lower back. She was also noted to have male pattern escutcheon with dark hairs spreading onto the thighs, clitoromegaly and no discrete adnexal masses on pelvic examination. A repeat transvaginal ultrasound revealed a low-level mass in the right ovary measuring 38 x 33 x 27 millimeters and two low-level densities in the left ovary measuring 8 x 8 x 7 and 7 x 7 x 7 millimeters. Repeat testosterone was 458 ng/dL (15-79 ng/dL).
The rapid onset and progression of hirsutism and virilizing signs accompanied by a markedly elevated serum testosterone suggests the possibility of an androgen-producing ovarian neoplasm or severe hyperthecosis. The patient was offered conservative approaches including a trial of a gonadotropin releasing hormone agonist to determine if androgen production was gonadotropin dependent and which is expected in hyperthecosis. Another conservative option explored with the patient included selective ovarian vein catheterization to determine which ovary was producing excess androgen, followed by unilateral oophorectomy of the affected ovary and removal of the mass on the contralateral ovary. Hysterectomy with removal of both ovaries was discussed with the patient because of the presence of bilateral ovarian masses, which required diagnosis and treatment. After thorough discussion she elected to proceed with a laparoscopic assisted vaginal hysterectomy with bilateral salpingooopherectomy. Pathology demonstrated a dermoid cyst of the right ovary and a steroid cell tumor, not otherwise specified, of the left ovary.
While hirsutism is usually the result of a benign condition, our patient had many concerning signs and symptoms. The patient had a history of chronic mild hirsutism, but over the five months prior to presentation she had the rapid onset and progression of male-pattern hair affecting the face, neck, chest, abdomen and thighs. She also had developed virilizing signs, with male-pattern hair loss, male escutcheon and clitoromegaly over the preceding five months. In addition, the patient also had amenorrhea of three years duration, central obesity, increased supraclavicular fat pads and moon facies, as well as abdominal striae. Laboratory tests demonstrated a markedly elevated testosterone (>200ng/dL in a premenopausal woman) but a normal adrenal evaluation.
This case illustrates the importance of a high level of suspicion for ovarian or adrenal neoplasm when patients have the rapid onset and progression of hirsutism and virilizing signs so treatment is not delayed. Elevated testosterone with normal dehydroepiandrosterone sulfate (DHEA-S) levels point to an ovarian source of androgens, whereas elevated DHEA-S points toward an adrenal source. The markedly elevated testosterone with normal adrenal evaluation in our patient suggested that the ovaries were the source of pathology.
The differential diagnosis in this case included hyperthecosis or an ovarian androgen-producing neoplasm. Hyperthecosis is a disorder of ovarian stroma that is most commonly seen in postmenopausal women but may blend with polycystic ovarian syndrome (PCOS) in younger women. The ovary undergoes uniform enlargement consisting of hypercellular stroma with luteinized theca cells scattered throughout the stroma. It is clinically similar to PCOS, although virilization may be striking and usually LH levels are normal.3 Treatment is either to suppress or remove the ovary. Hyperthecosis may be resistant to suppression with oral contraception pills but will usually respond to gonadotropin-releasing hormone agonists (GnRH-a) like leuprolide.
Androgen-producing neoplasms of the ovary are usually palpable on physical examination and typically the androgen levels are not suppressed by treatment with oral contraceptive pills or GnRH-a. After discussion of alternatives our patient elected to proceed with hysterectomy and bilateral oophorectomy due to the markedly elevated testosterone and rapid progression of her virilizing signs and symptoms. The pathology demonstrated an androgen-producing neoplasm, not otherwise specified, of the ovary. The patient had rapid, significant improvement in her signs and symptoms. These androgen-producing tumors of the ovary may have malignant potential and thus the importance of their complete removal and pathologic evaluation.4
Hirsutism is a common problem that can be particularly distressing, causing significant psychological morbidity.5 The differential diagnosis of hirsutism includes both common and infrequent etiologies. Common causes of hirsutism include familial, idiopathic and PCOS. Uncommon causes of hirsutism include virilizing ovarian tumors, hyperthecosis, luteoma of pregnancy, late onset congenital adrenal hyperplasia, Cushing’s syndrome, virilizing adrenal adenoma, adrenal carcinoma, pituitary adenoma, ectopic ACTH or CRH production or hyperprolactinemia. Patients with hyperandrogenism will commonly have irregular menses. In fact, if the patient has regular menses, it points more to familial hirsutism.
The evaluation of hirsutism entails a careful history exploring the onset and progression of hair growth, menstrual cycle history, assessment of fertility (pregnancy history), medication use and family history. Physical examination includes inspection for excess hair, presence of acne, body habitus, and any evidence of virilizing signs (clitoromegaly, deepening of voice, increased muscle mass, breast atrophy, and temporal hair loss), assessing for signs of Cushing’s syndrome (central obesity, proximal muscle weakness, muscle wasting, striae, dorsocervical and/or supraclavicular fat pads), assessing for signs of hyperinsulinemia and appraising for abdominal or ovarian masses.
A common method of assessing and documenting androgen-dependent hair growth is the semi-quantitative Ferriman-Gallwey scoring system. The nine body areas most sensitive to androgen (upper lip, chin, chest, abdomen, pubic, arms, thighs, upper back and lower back) are scored from 0 (no hair) to 4 (frankly virile) and then summed to provide a hirsutism score. A score of 8 to 15 is classified as mild hirsutism, while moderate hirsutism is a score greater than 15. This patient had severe hirsutism with virilizing signs. Therefore, it was not necessary to grade her level of hirsutism.
Women with gradually progressing mild hirsutism, regular menses, family history of hirsutism and normal physical examination do not require laboratory evaluation.6 In these patients, one may consider a trial of cosmetic, dermatologic or oral contraceptive therapy.
Women with sudden onset, rapidly progressive or moderate to severe hirsutism as well as when associated with menstrual irregularity, infertility, central obesity, acanthosis nigricans or clitoromegaly should be tested for elevated androgen levels.6 Plasma testosterone is best assessed in the early morning on days four through 10 of the menstrual cycle in regularly cycling women. If the total testosterone is normal in the presence of risk factors for hyperandrogenism or the presence of hirsutism that progresses in spite of therapy, measuring an early morning plasma total and free testosterone in a reliable specialty laboratory is indicated.6 In cases of obesity and severe insulin resistance, sex hormone-binding globulin may be decreased, resulting in an artificially low or normal total testosterone, when the free testosterone is actually elevated. Free testosterone is a more sensitive, laboratory test for the detection of hyperandrogenism, but requires equilibrium dialysis for the best precision and accuracy. From a clinical standpoint a total testosterone is sufficient, since when it is elevated it correlates well with free testosterone and one is using this test to screen for testosterone producing tumors. In patients with markedly elevated testosterone levels one is concerned about the possibility of an ovarian androgen-producing tumor.7
When androgen excess is discovered, the most common cause is PCOS, while only 0.2 percent of hirsute patients are found to have androgen-secreting neoplasms.2 Rapid onset hirsutism and virilizing features are suggestive of neoplasms of the ovaries or adrenals. Androgen levels that suggest an ovarian androgen-secreting neoplasm are normal DHEA-S levels, and testosterone greater than 200 ng/dL (or 2 times the upper limit of normal) in premenopausal women and greater than 100 ng/dL in postmenopausal women. An elevated DHEA-S suggests an adrenal source of excess androgen production. Pelvic ultrasonography or adrenal protocol CT may be indicated in these patients.
PCOS is the most common endocrinopathy, affecting 5 to 8 percent of reproductive-aged females, and they may present with moderate to severe hirsutism. Diagnosis requires two of the following three criteria: oligoor anovulation, increased androgens either clinically or biochemically and polycystic ovaries on ultrasound evaluation. The diagnosis requires that other causes of irregular menstrual cycles and hyperandrogenism are excluded.8 An elevated LH/FSH ratio is common but not necessary in PCOS. Hyperinsulinemia and other metabolic syndromes are also associated with PCOS.
Treatment of hirsutism depends on the underlying cause. Referral may be indicated for suspected neoplasms, PCOS or adrenal pathology. For familial and idiopathic hirsutism in which cosmetic therapies are not adequate, pharmacologic treatment, along with direct hair removal methods, are recommended.6 Pharmacologic therapies shown to reduce hirsutism scores include oral contraceptives or antiandrogens as monotherapies or as combination therapy.6
Oral contraceptives reduce hyperandrogenism by suppressing LH, stimulating production of sex hormone-binding globulin, slightly reducing adrenal androgen secretion and slightly blocking androgen receptors. Drospirenone, which is also a weak antiandrogen, is a newer progestin used in several OCPs.
Antiandrogens such as spironolactone, cyproterone acetate (not available in the U.S.), drospirenone, finasteride and flutamide have shown efficacy in trials.6,9 Antiandrogens should not be used without adequate contraception due to teratogenic potential. Spironolactone is an aldosterone antagonist that exhibits dose-dependent inhibition of the androgen receptor and inhibition of 5-alpha reductase. Finasteride inhibits 5-alpha reductase activity. Flutamide is not recomended as first-line therapy due to concern with hepatic toxicity.4,5 Eflornithine HCL 13.9 percent cream is a novel topical agent used twice daily with successful inhibition of unwanted facial hair usually in four to eight weeks. Pharmacologic therapies for hirsutism should include a six-month trial before making changes in dose or changing or adding medications.6
Local cosmetic therapies include temporary methods such as plucking, waxing and shaving, as well as permanent methods such as electrolysis or laser destruction of the hair follicle. Local cosmetic therapies work best in combination with pharmacologic suppression of hair growth. It is important to remind the patient that hair growth is asynchronous, so control will require time and multiple applications of local cosmetic therapy to achieve the desired effect.
In cases of virilization with markedly elevated androgens, it is important to locate the cause of excess androgen production. In patients with an ovarian androgen producing tumor, removal of the tumor will usually restore androgen levels to normal female levels. Once the levels are restored to normal then local destruction of the terminal hair follicles will help with the hirsutism. For patients with significant clitoromegaly, a clitoral recession will return the clitoris to a more normal size and maintain normal neurologic function. In patients with hyperthecosis, treatment can be aimed at suppressing ovarian function with oral contraceptive pills, progestins or gonadotropin releasing hormone agonists. Patients with an androgen-producing adrenal adenoma or carcinoma will require surgical diagnosis and therapy, as well as chemotherapy in the case of adrenal carcinoma. In patients with congenital adrenal hyperplasia glucocorticoids and possibly mineralocorticoids, if salt-wasting, will suppress adrenal androgen production. In patients with CAH, clitoromegaly, as well as labioscrotal fusion, require clitoroplasty and vaginal reconstructive surgery.
Most cases of hirsutism result from benign conditions. The prompt and thorough evaluation of patients with hirsutism is important to determine the specific etiology causing this sign. This case reminds one of the importance of having a high level of suspicion for neoplasms of the ovary or adrenal when there is rapid onset or progression of hirsutism and virilizing signs.
The authors would like to thank Diane Sneed, MD, of Physicians Laboratory, Ltd., in Sioux Falls, S.D., for
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About the Authors:
Emily Winterton, MD, is a resident in obstetrics and gynecology at the National Naval Medical Center in Bethesda, Md. She was a fourth-year medical student at the Sanford School of Medicine of The University of South Dakota at the time the article was written.
Kathleen Eyster, PhD, is Professor of Obstetrics and Gynecology at the Sanford School of Medicine of The University of South Dakota.
Keith A. Hansen, MD, is Chair, Obstetrics and Gynecology at the Sanford School of Medicine of The University of South Dakota; a reproductive endocrinologist with Sanford Health in Sioux Falls, S.D., and co-editor of South Dakota Medicine.
May 2011 165 Winterton Journal
©Copyright Emily Winterton, MD; Kathleen Eyster, PhD; Keith A. Hansen, M.D.