Hirsutism, Sertoli–Leydig Cell Tumor Case File

Hirsutism, Sertoli–Leydig Cell Tumor Case File

Eugene C. Toy, MD, Patti Jayne Ross, MD, Benton Baker III, MD, John C. Jennings, MD

CASE 53

A 42-year-old parous woman has noticed increasing hair growth on her face and abdomen over the past 6 months. She denies the use of steroid medications, weight changes, or a family history of hirsutism. Her menses previously had been monthly, and now occur every 35 to 70 days. Her past medical and surgical histories are unremarkable. On examination, her thyroid is normal to palpation. She has excess facial hair and male-pattern hair on her abdomen. Acne is also noted on the face. The cardiac and pulmonary examinations are normal. The abdominal examination reveals no masses or tenderness. Examination of the external genitalia reveals possible clitoromegaly. Pelvic examination shows a normal uterus and cervix and an 8-cm, right adnexal mass.

» What is the most likely diagnosis?

» What is the probable management?

ANSWER TO CASE 53:

Hirsutism, Sertoli–Leydig Cell Tumor                                           

Summary: A 42-year-old woman with a 6-month history of increasing hirsutism and irregular menses. She denies the use of steroid medications, weight changes, or a family history of hirsutism. Pelvic examination shows an 8-cm, right adnexal mass.

• Most likely diagnosis: An ovarian tumor, probable Sertoli–Leydig cell tumor.
• Probable management: Ovarian cancer (surgical) staging.

ANALYSIS

Objectives

1. Understand the differential diagnosis of hirsutism.
2. Know the work-up and approach to a woman with virilism and hirsutism.
3. Know the typical history and physical examination and treatment for the various causes of hirsutism.

Considerations

This 42-year-old woman has the onset of excess male-pattern hair over the past 6 months, as well as features of virilism (clitoromegaly). This is evidence of excess androgens. The rapid onset speaks of a tumor. Adrenal or ovarian tumors are possibilities. This woman has a large adnexal mass, and so the diagnosis is straightforward. She has irregular menses because of the androgen effect of inhibiting ovulation. The patient does not have the stigmata of Cushing disease, such as hypertension, buffalo hump, abdominal striae, and central obesity. Likewise, she does not take any medications containing anabolic steroids. Polycystic ovarian syndrome (PCOS) is the most common cause of hyperandrogenism; however, PCOS does not fit this clinical scenario. PCOS most commonly presents with an insidious onset of hirsutism and irregular menses since menarche. A Sertoli– Leydig cell tumor of the ovary is a solid stromal type of tumor, the androgen counterpart of granulosa-theca cell tumor (which secretes estrogens). These tumors are usually of low malignant potential and slow growing, but nevertheless may metastasize and often recur. As with all ovarian malignancies, surgical staging is the treatment of choice.

APPROACH TO:

Hirsutism                                              

DEFINITIONS

HIRSUTISM: Excessive male-pattern hair in a woman.

VIRILISM: Androgen effect other than hair pattern, such as clitoromegaly, male balding, deepening of the voice, and acne.

CLINICAL APPROACH

Hirsutism should be viewed both as an endocrine and a cosmetic problem. It is most commonly associated with anovulation; however, other causes of increased androgen levels, such as adrenal and ovarian diseases, need to be ruled out. The most sensitive marker of excess androgen production is hirsutism, followed by acne, oily skin, increased libido, and virilization. Virilization consists of clitoromegaly, deepening of the voice, balding, increased muscle mass, and male body habitus. Adrenal hyperplasia or androgen-secreting tumors of the adrenal gland or ovary are causes of virilization. Of note, virilization is rarely associated with PCOS. The treatment depends on the underlying etiology.

    The pattern of hair growth is genetically predetermined. Differences in hair growth between ethnic groups are secondary to variations in hair follicle concentration and 5-alpha-reductase activity. Hair growth can be divided into three phases: anagen (growing phase), catagen (involution phase), and telogen (quiescent phase). The hair length is determined by the length of the anagen phase. The stability of hair is determined by the length of the telogen phase. Hairs found on the face, axilla, chest, breast, pubic area, and anterior thighs are termed “sex hair” because they respond to sex hormones. Androgens (especially testosterone) initiate the growth of pubic hair and increase the diameter and pigmentation of pubic hair. Androgens may be produced by the ovary, adrenal gland, or by peripheral conversion. Dehydroepiandrosterone sulfate (DHEA-S) is derived almost exclusively from the adrenal gland. Dihydrotestosterone (DHT) is metabolized from testosterone by 5-alpha-reductase; increased activity of 5-alpha-reductase leads to an increase in DHT and stimulation of hair growth. The majority of testosterone is bound to sex hormone-binding globulin (SHBG), and it is the unbound portion that is primarily responsible for androgenicity. Hyperandrogenism decreases SHBG, and thus, exacerbates hirsutism.

    The appearance and cosmetic changes associated with hirsutism depend on the number of follicles present, ratio of growth to resting phases, asynchrony of growth cycles, and thickness and degree of pigmentation of individual hairs. The history should focus on the onset and duration of symptoms (faster growth is associated with tumors of the adrenal gland and ovary, whereas slow onset since menarche is more likely polycystic ovarian syndrome). The severity of symptoms should also be characterized (eg, virilization is rare and is usually associated with androgen-secreting tumors). The regularity of the menses and symptoms of thyroid disease should also be sought. The physical examination should focus on the location of hair growth and its severity, thyromegaly, body shape and habitus, the presence of breast discharge, skin changes (acanthosis or abdominal striae), adnexal or abdominal masses, and the external genitalia. Helpful laboratory tests include assays for serum testosterone, DHEA-S, 17-hydroxyprogesterone (which is elevated with congenital adrenal hyperplasia), prolactin, and thyroid-stimulating hormone (TSH). A markedly elevated testosterone level suggests an androgen-secreting ovarian tumor, such as a Sertoli–Leydig cell tumor. With a high DHEA-S level, the examiner should be suspicious of an adrenal process, such as adrenal hyperplasia or a tumor.

The differential diagnosis for hirsutism (Table 53– 1) includes anovulation, lateonset adrenal hyperplasia, androgen-secreting tumors (adrenal or ovarian in origin), Cushing disease, medications, thyroid disease, and hyperprolactinemia.

    A genetic defect in the enzyme 21-hydroxylase causes most of the cases of congenital adrenal hyperplasia (CAH). While classic CAH is the most common cause of ambiguous genitalia in the newborn, late onset of nonclassical CAH can present in adult women with symptoms of hirsutism and anovulation. An elevated morning fasting 17-hydroxyprogesterone level is highly suggestive of CAH. Treatment depends on the etiology; however, in general, the goal is to decrease the amount of DHT available. This can be accomplished by inhibiting adrenal or ovarian androgen secretion, changing SHBG binding, impairing peripheral conversion of androgen to active androgen, and inhibiting activity at target tissues. Treatment options include weight loss, combined oral contraception pills, spironolactone (a diuretic that is an androgen antagonist), progesterone-containing medications, electrolysis, laser vaporization, waxing, and shaving. The patient must be warned that there is a slow response to treatment with medications (an average of 6 months). To help with more immediate results, nonmedical therapies (waxing and shaving) may be used initially until the new medication begins to work effectively.

COMPREHENSION QUESTIONS

53.1 A 6-year-old girl is noted to have breast development and vaginal spotting. No abnormal hair growth is noted. A 10-cm ovarian mass is palpated on rectal examination. Which of the following is the most likely diagnosis?

A. Benign cystic tumor (dermoid)

B. Idiopathic precocious puberty

C. Sertoli–Leydig cell tumor

D. Congenital adrenal hyperplasia

E. Granulosa-theca cell tumor

53.2 A 15-year-old G0P0 girl complains of increasing hair over her face and chest. She also has a deepening voice and clitoromegaly. There have been two neonatal deaths in the family. Which of the following is the best diagnostic test for the likely diagnosis?

A. Testosterone level

B. Dexamethasone suppression test

C. 17-Hydroxyprogesterone level

D. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels

E. Karyotype

53.3 A 22-year-old nulliparous woman with irregular menses of 7 years’ duration complains of primary infertility. She has a family history of diabetes. She has mild hirsutism on examination. Which of the following is the most likely therapy?

A. Cortisol and mineralocorticoid replacement

B. Excision of an adrenal tumor

C. Surgical excision of an ovarian tumor

D. Oral clomiphene citrate

E. Intrauterine insemination

53.4 A 24-year-old woman complains of bothersome hirsutism and skipping periods. She does not have evidence of voice changes, hair loss, or clitoromegaly. The pelvic examination does not reveal adnexal masses. The serum DHEA-S, testosterone, and 17-hydroxyprogesterone levels are normal. The LH-to- FSH ratio is 1:1. Which of the following is the most likely diagnosis?

A. Polycystic ovarian syndrome

B. Familial hirsutism

C. Ovarian tumor

D. Adrenal tumor

E. Cushing syndrome

ANSWERS

53.1 E. Isosexual (no virilization) precocious puberty with an adnexal mass usually is a granulosa cell tumor of the ovary. Dermoid cysts are also found in the ovary. They present as a pelvic mass that causes pain due to its rapidly enlarging size, however, they do not cause isosexual precocious puberty. A Sertoli–Leydig cell tumor is the androgen counterpart to the granulose-theca cell tumor. With a Sertoli– Leydig cell tumor, testosterone levels are markedly elevated, and patients typically present with hirsutism, virilism, and an adnexal mass. Congenital adrenal hyperplasia is the most common cause of ambiguous genitalia in the newborn; however, late onset can present in adult women with symptoms of hirsutism and anovulation.

53.2 C. The most common neonatal endocrine cause of death (salt wasting) is congenital adrenal hyperplasia (21-hydroxylase deficiency). An elevated testosterone level would be found with a Sertoli–Leydig cell tumor. A dexamethasone suppression test is used in the diagnosis of Cushing syndrome. An elevated LH-to-FSH ratio is found with PCOS. A karyotype may be used in finding the etiology behind a young girl’s presentation of primary amenorrhea or pubertal delay.

53.3 D. This patient most likely has PCOS; the initial treatment for infertility is clomiphene citrate. Since the symptoms were not of rapid onset, the etiology is not likely to involve a tumor. Intrauterine insemination is usually indicated for the rare cervical factor infertility, and not ovulatory dysfunction.

53.4 A. Polycystic ovarian syndrome is the most common cause of hirsutism and irregular menses. Treatment may be spironolactone (androgen antagonist) and oral contraceptives. Familial hirsutism usually is not associated with oligomenorrhea. Symptoms do not correlate with an ovarian tumor (since the patient has abnormal hair growth, hirsutism); also, laboratory values indicate normal adrenal function, thus ruling out adrenal tumor and Cushing syndrome. Notably, a normal LH:FSH ratio does not rule out PCOS, although often there is an increased LH:FSH ratio.

    CLINICAL PEARLS    

» The rapid onset of hirsutism or virilization usually indicates the presence of an androgen-secreting tumor. » The two most common locations of androgen production and secretion are the ovary and the adrenal gland. » The most common cause of hirsutism and irregular menses is polycystic ovarian syndrome. » The most common cause of ambiguous genitalia in the newborn is congenital adrenal hyperplasia, usually due to 21-hydroxylase enzyme deficiency. » Hyperandrogenism in the face of an adnexal mass usually indicates a Sertoli– Leydig cell tumor of the ovary, and is treated surgically.

REFERENCES

Alexander CJ, Mathur R, Laufer LR, Aziz R. Amenorrhea, oligomenorrhea, and hyperandrogenic disorders. In: H acker NF, Gambone JC, Hobel CJ, eds. Essentials of Obstetrics and Gynecology. 6th ed. Philadelphia, PA: Saunders; 2012:355-367. 

Schorge W, Schaffer J, Horson L, et al. Ovarian germ cell and sex cord stromal tumors. In: Schorge W, Schaffer J, Horson L, eds. Williams Gynecology. 2nd ed. New York, NY: McGraw-Hill; 2012: 738-754. Speroff L. Hirsutism. In: Fritz MA, 

Speroff L. eds. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2010:499-530.

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