Gynecology_Novak

Gynecology_Novak. When laboratory testing for the assessment of hirsutism is indicated, either a bioavailable testosterone level (includes a total testosterone, SHBG, and albumin level) or a calculated free testosterone level (if albumin levels are assumed to be normal) provides the most accurate assessment of the androgen effect derived from testosterone. In clinical situations requiring a testosterone evaluation, the addition of 17-hydroxyprogesterone will screen for adult onset adrenal hyperplasia, when indicated (Table 31.2). When hirsutism is accompanied by absent or abnormal menstrual periods, assessment of prolactin and thyroid-stimulating hormone (TSH) values are required to diagnose an ovulatory disorder. Hypothyroidism and hyperprolactinemia may result in reduced levels of SHBG and may increase the fraction of unbound testosterone levels, occasionally resulting in hirsutism. In cases of suspected Cushing syndrome, patients should undergo screening with a 24-hour urinary cortisol (most


Gynecology_Novak

Gynecology_Novak. the fraction of unbound testosterone levels, occasionally resulting in hirsutism. In cases of suspected Cushing syndrome, patients should undergo screening with a 24-hour urinary cortisol (most sensitive and specific) assessment or an overnight dexamethasone suppression test. For this test, the patient takes 1 mg of dexamethasone at 11 p.m., and a blood cortisol assessment is performed at 8 a.m. the next day. Cortisol levels of 2 μg/dL or higher after overnight dexamethasone suppression require a further workup for evaluation of Cushing syndrome. Elevated 17hydroxyprogesterone (17-OHP) levels identify patients who may have AOAH, found in 1% to 5% of hirsute women. The 17-OHP levels can vary significantly within the menstrual cycle, increasing in the periovulatory period and luteal phase, and may be modestly elevated in PCOS. Standardized testing requires early morning testing during the follicular phase.


Gynecology_Novak

Gynecology_Novak. According to the Endocrine Society clinical guidelines, patients with morning follicular phase 17-OHP levels of less than 300 ng/dL (10 nmol/L) are likely unaffected. When levels are greater than 300 ng/dL but less than 10,000 ng/dL (300 nmol/L), ACTH testing should be performed to distinguish between PCOS and AOAH. Levels greater than 10,000 ng/dL (300 nmol/L) are virtually diagnostic of congenital adrenal hyperplasia.


Gynecology_Novak

Gynecology_Novak. Precocious pubarche precedes the diagnosis of adult onset congenital adrenal hyperplasia in 5% to 20% of cases. Measurement of 17-OHP should be performed in patients presenting with precocious pubarche, and a subsequent ACTH stimulation test is recommended if basal 17-OHP is greater than 200 ng/dL. A study using a 200 ng/dL threshold for basal 17-OHP plasma levels to prompt ACTH stimulation testing offered 100% (95% confidence interval [CI], 69– 100) sensitivity and 99% (95% CI, 96–100) specificity for the diagnosis of adult onset congenital adrenal hyperplasia within the cohort with precocious puberty (6).


Gynecology_Novak

Gynecology_Novak. Because increased testosterone production is not reliably reﬂected by total testosterone levels, the clinician may choose to rely on typical male pattern hirsutism as confirmation of its presence, or may elect measures that reﬂect levels of free or unbound testosterone (bioavailable or calculated free testosterone levels). Total testosterone does serve as a reliable marker for testosterone-producing neoplasms. Total testosterone levels greater than 200 ng/dL should prompt a workup for ovarian or adrenal tumors. Although the ovary is the principal source of androgen excess in most of PCOS patients, 20% to 30% of patients with PCOS will demonstrate supranormal levels of DHEAS. Measuring circulating levels of DHEAS has limited diagnostic value, and overinterpretation of DHEAS levels should be avoided (7).


Gynecology_Novak

Gynecology_Novak. In the past, testing for androgen conjugates (e.g., 3α-androstenediol G [3α-diol G] and androsterone G [AOG] as markers for 5α-reductase activity in the skin) was advocated. Routine ≥9 Adult onset adrenal hyperplasia >1000 <10,000 ng/dL Hirsutism Ferriman – Gallwey score ≤8 24-hour urinary cortisol Trial of OCPs, cosmetic, and dermatologic treatments >45 g/day ACTH stimulation test >300 ng/dL Cushing evaluation Plus: Moon facies, plethora, striae, dorsoclavicular or supraclavicular fat pads, proximal muscular weakness Assess for PCOS, AOAH, HAIR-AN, ovarian or adrenocortical tumor or other* 17-OH progesterone bioavailable testosterone (total and free included) No response 48-hour low-dose dexamethasone suppression: 40% suppression of T  11-desoxycortisol >7 ng/mL,  24-hour urinary cortisol >45 g/day,  DHEAS >360 g/dL Total T >200 ng/dL Elevated values consistent with Ovarian Tumor or Adrenocortical Tumor Total T >80 <150 ng/dL, bioavailable or free T mildly elevated, endocrine


Gynecology_Novak

Gynecology_Novak. >45 g/day,  DHEAS >360 g/dL Total T >200 ng/dL Elevated values consistent with Ovarian Tumor or Adrenocortical Tumor Total T >80 <150 ng/dL, bioavailable or free T mildly elevated, endocrine consultation PCOS, hyperthecosis, HAIR-AN Radiologic consultation on current imaging techniques Total T >200 ng/dL  bioavailable or free T >6.85 pg/mL  Or free endocrine consultation Total T normal or mildly elevated, bioavailable T normal or mildly elevated PCOS, idiopathic hirsutism Adrenal androgen secreting tumor  usually >1.5 cm and detectable by CT (sensitivity 70%–90%).  Ovarian androgen-secreting tumors usually <2 cm.  Selective venous sampling may be required.


Gynecology_Novak

Gynecology_Novak. Figure 31.3 Evaluation of hirsute women for hyperandrogenism. Evaluation includes more than the assessment of the degree of hirsutism. When hirsutism is moderate (>9) or severe or if mild hirsutism is accompanied by features that suggest an underlying disorder, elevated androgen levels should be ruled out. Disorders to be considered include endocrinopathies, of which PCOS is the most common, and neoplasms. Plasma testosterone is best assessed in the early morning on day 4 to 10 in regularly cycling women. A 17-hydroxyprogesterone is also indicated when symptoms warrant a bioavailable testosterone measurement. *3β-hydroxysteroid dehydrogenase deficiency in severe forms presents with mineralocorticoid and cortisol deficiency. Mild forms are diagnosed with a mean post-ACTH(1-24) stimulation: 17-hydroxypregnenolone/17-hydroxyprogesterone ratio of 11 compared to 3.4 in normals. 11β-hydroxylase deficiency presents with hypertension in the first years of life in two thirds of patients. The


Gynecology_Novak

Gynecology_Novak. 17-hydroxypregnenolone/17-hydroxyprogesterone ratio of 11 compared to 3.4 in normals. 11β-hydroxylase deficiency presents with hypertension in the first years of life in two thirds of patients. The mild form presents with vitalization or precocious puberty without hypertension. Undiagnosed adults demonstrate hirsutism, acne, and amenorrhea. Diagnosis is confirmed with an 11-desoxycortisol level >25 ng/mL 60 minutes after ACTH(1-24) stimulation. ACTH, adrenocorticotropic hormone; AOAH, adult-onset adrenal hyperplasia; DHEAS, dehydroepiandrosterone sulfate; HAIR-AN, hyperandrogenemia, insulin resistance-acanthosis nigricans. (See references 2–11,15.)


Gynecology_Novak

Gynecology_Novak. Table 31.1 Medications Associated with Hirsutism determination of androgen conjugates to assess hirsute patients is not recommended, because hirsutism itself is an excellent bioassay of free testosterone action on the hair follicle and because these androgen conjugates arise from adrenal precursors and are likely markers of adrenal and not ovarian steroid production (8).


Gynecology_Novak

Gynecology_Novak. In the zona reticularis layer of the adrenal cortex, DHEAS is generated by SULT2A1 (9). This layer of the adrenal cortex is thought to be the primary source of serum DHEAS. DHEAS levels decline as a person ages and the reticularis layer diminishes in size. In most laboratories, the upper limit of a DHEAS level is 350 μg/dL (9.5 nmol/L). A random sample is sufficient because the level of variation is minimized as a result of the long half-life characteristic of sulfated steroids. DHEAS is used as a screen for androgen-secreting adrenocortical tumors; however, moderate elevations are a common finding in the presence of PCOS, obesity, and stress, which reduces specificity (10).


Gynecology_Novak

Gynecology_Novak. A study of women with androgen-secreting adrenocortical tumors (ACT-AS) (N = 44), compared to women with nontumor androgen excess (NTAE) (N = 102), sheds additional light on the choice of hormones used to screen for an adrenocortical tumor. In the study, the demographics and the prevalence of hirsutism, acne, oligomenorrhea and amenorrhea were not different in each group. Free testosterone (free T) was the most commonly elevated androgen in ACT-AS (94%), followed by androstenedione (A) (90%), DHEAS (82%), and total testosterone (total T) (76%), Table 31.2 Normal Values for Serum Androgensa Free testosterone (calculated) 0.6–6.8 pg/mL Percentage free testosterone 0.4–2.4% Bioavailable testosterone 1.6–19.1 ng/dL Albumin 3,300–4,800 mg/dL


Gynecology_Novak

Gynecology_Novak. Free testosterone (calculated) 0.6–6.8 pg/mL Percentage free testosterone 0.4–2.4% Bioavailable testosterone 1.6–19.1 ng/dL Albumin 3,300–4,800 mg/dL SHBG, sex hormone–binding globulin. aNormal values may vary among different laboratories. Free testosterone is calculated using measurements for total testosterone and sex hormone–binding globulin, whereas bioavailable testosterone is calculated using measured total testosterone, sex hormone–binding globulin, and albumin. Calculated values for free and bioavailable testosterone compare well with equilibrium dialysis methods of measuring unbound testosterone when albumin levels are normal. Bioavailable testosterone includes free plus very weakly bound (non-SHBG, nonalbumin) testosterone. Bioavailable testosterone is the most accurate assessment of bioactive testosterone in the serum without performing equilibrium dialysis.


Gynecology_Novak

Gynecology_Novak. Table 31.3 Sensitivity and Specificity of Basal Hormone Levels in the Evaluation of Female Patients with Androgen-secreting Adrenocortical Tumors (ACT-AS) and Nontumor Causes of Androgen Excess (NTAE) Thresholds were selected using Youden’s index, as described in the methods. a CI: 95% confidence intervals. (Reprinted with permission from d’Alva CB, Abiven-Lepage G, Viallon V, et al. Sex steroids in androgen-secreting adrenocortical tumors: clinical and hormonal features in comparison with non-tumoral causes of androgen excess. Eur J Endocrinol 2008;159:641–647.


Gynecology_Novak

Gynecology_Novak. and all three androgens were simultaneously elevated in 56% of the cases. Serum androgen levels became subnormal in all ACT-AS patients after the tumor was removed. In nontumor androgen excess alone, the most commonly elevated androgen was androstenedione (93%), while all three androgens (T, A, and DHEAS) were elevated in only 22% of the cases. Free testosterone values above 6.85 pg/mL (23.6 pmol/L) had the best diagnostic value for ACT-AS (sensitivity 82%; CI, 57%–96%; specificity 97%, CI, 91%–100%) (Table 31.3). The large overlap of androstenedione, testosterone, and DHEAS levels between ACT-AS and androgen excess groups suggests that thoughtful consideration should be employed when choosing hormone studies for this evaluation (11).


Gynecology_Novak

Gynecology_Novak. The heterogeneity of hormone secretion patterns in the adrenocortical tumor group reveals the complexities of hormone level screening for adrenocortical tumors: 7 of 44 patients (15.9%) had tumors secreting androgens alone, 2 of 44 (4.5%) had tumors secreting androgens and estrogens, 28 of 44 (63.6%) had tumors secreting both androgens and cortisol, and 7 of 44 (15.9%) had tumors secreting androgens, cortisol, and estrogens. Compound S or 11-desoxycortisol was increased (≥10 ng/mL or 28.9 nmol/L) in 23 of 27 ACT-AS patients (85%); 20 of 21 patients with malignant tumors, and 3 of 6 patients with apparently benign tumors, although 11-desoxycortisol was normal and inferior to 6 ng/mL (17.3 nmol/L) in 35 of 35 nontumor androgen excess patients (100%). Youden’s index displayed that a 11-desoxycortisol level above 7 ng/mL (20.2 nmol/L) has a sensitivity of 89% (95% CI, 71%–98%) and a specificity of 100% (95% CI, 90%–100%) for the detection of ACT-AS (11,12).


Gynecology_Novak

Gynecology_Novak. When clinical signs of androgen excess reach the point of virilization or the free testosterone level is above 6.85 pg/mL (23.6 pmol/L), follow-up testing with a 11-desoxycortisol (>7 ng/mL), DHEAS (>3.6 μg/mL), and 24-hour urinary cortisol (>45 μg per day) are the most sensitive and specific for the detection of an androgen-secreting adrenocortical tumor. Careful consideration of the sensitivity and specificity, diurnal variation, and age-related variation of potentially measureable androgens will aid in choosing the most useful measurements (Table 31.3).


Gynecology_Novak

Gynecology_Novak. PCOS is arguably one of the most common endocrine disorders in women of reproductive age, affecting 5% to 10% of women worldwide. This familial disorder appears to be inherited as a complex genetic trait (13). It is characterized by a combination of hyperandrogenism (either clinical or biochemical), chronic anovulation, and polycystic ovaries. It is frequently associated with insulin resistance and obesity (14). PCOS receives considerable attention because of its high prevalence and possible reproductive, metabolic, and cardiovascular consequences. It is the most common cause of hyperandrogenism, hirsutism, and anovulatory infertility in developed countries (15,16). The association of amenorrhea with bilateral polycystic ovaries and obesity was first described in 1935 by Stein and Leventhal (17). Its genetic origins are likely polygenic and/or multifactorial (18).


Gynecology_Novak

Gynecology_Novak. Diagnostic Criteria In an international conference on PCOS organized by the National Institutes of Health (NIH) in 1990, diagnostic criteria for PCOS were based on consensus rather than clinical trial evidence. Their diagnostic criteria recommended clinical and/or biochemical evidence of hyperandrogenism, chronic anovulation, and exclusion of other known disorders. These criteria were an important initial step in standardizing diagnosis and led to a number of landmark randomized clinical trials in PCOS (19). Since the 1990 NIH-sponsored PCOS conference, evolving perception is that the syndrome may constitute a broader spectrum of signs and symptoms of ovarian dysfunction than those set forth in the original NIH diagnostic criteria. The 2003 Rotterdam Consensus Workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology (Table 31.4).


Gynecology_Novak

Gynecology_Novak. It is recognized that women with regular cycles, hyperandrogenism, and PCO morphology may be part of the syndrome. Some women with the syndrome will have PCO morphology without clinical evidence of androgen excess, but will display evidence of ovarian dysfunction with irregular cycles. In this new schema, PCOS remains a diagnosis of exclusion with the need to rule out other disorders that mimic the PCOS phenotype (19). Using the Rotterdam PCOS Diagnostic Criteria, the presence of two of the three criteria is sufficient to diagnosis PCOS: menstrual cycle anomalies (amenorrhoea, oligomenorrhea), clinical and/or biochemical hyperandrogenism, and/or the ultrasound appearance of polycystic ovaries after all other diagnoses are ruled out. Other pathologies that can result in a POCS phenotype include AOAH, adrenal or ovarian neoplasm, Cushing syndrome, hypo-or hypergonadotropic disorders, hyperprolactinemia, and thyroid disease (Fig. 31.4).


Gynecology_Novak

Gynecology_Novak. All other frequently encountered manifestations offer less consistent findings and therefore qualify only as minor diagnostic criteria for PCOS. They include elevated LH-to-FSH (follicle-stimulating hormone) ratio, insulin resistance, perimenarchal onset of hirsutism, and obesity. Clinical hyperandrogenism includes hirsutism, male pattern alopecia, and acne (19). Hirsutism occurs in approximately 70% of patients with PCOS in the United States and in only 10% to 20% of patients with PCOS in Japan (20,21). A likely explanation for this discrepancy is the genetically determined differences in skin 5α-reductase activity (22,23). Nonclassic adrenal hyperplasia and PCOS may present with similar clinical features. It is important to measure the basal follicular phase 17-hydroxyprogesterone level in all women presenting Table 31.4 Revised Diagnostic Criteria of Polycystic Ovary Syndrome 1. 2. Clinical and/or biochemical signs of hyperandrogenism and exclusion of other etiologies.


Gynecology_Novak

Gynecology_Novak. Table 31.4 Revised Diagnostic Criteria of Polycystic Ovary Syndrome 1. 2. Clinical and/or biochemical signs of hyperandrogenism and exclusion of other etiologies. Revised 2003 criteria (2 out of 3) 1. 2. Clinical and/or biochemical signs of hyperandrogenism 3. Polycystic ovaries and exclusion of other etiologies (congenital adrenal hyperplasia, androgen-secreting tumors, Cushing’s syndrome) From Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25, with permission.


Gynecology_Novak

Gynecology_Novak. Polycystic ovary syndrome Ancillary studies Risk assessment for endometrial carcinoma Risk assessment for glucose intolerance Fasting cholesterol, HDL cholesterol, triglycerides, LDL cholesterol Risk assessment for obstructive sleep apnea Endometrial biopsy if risk increased Oral glucose-tolerance test if risk increased Polysomnography if risk increased Two of the following disorders confirmed:  Oligomenorrhea or amenorrhea  Hyperandrogenism (hursuitism, acne, alopecia)  Hyperandrogenemia (elevated levels of free or total T)  Polycystic ovaries on ultrasound All of the following disorders ruled out:  Hyperprolactinemia  Nonclassic congenital adrenal hyperplasia  Cushing’s syndrome  Androgen-secreting neoplasm  Acromegaly Figure 31.4 Diagnostic algorithm for polycystic ovary syndrome. (From Rosenfield RL. Clinical practice. Hirsutism. N Engl J


Gynecology_Novak

Gynecology_Novak. Med 2005;353:2578–2588, with permission.) with hirsutism to exclude the presence of nonclassic congenital adrenal hyperplasia, regardless of the presence of polycystic ovaries or metabolic dysfunction (24). The menstrual dysfunction in PCOS arises from anovulation or oligo-ovulation and ranges from amenorrhea to oligomenorrhea. Regular menses in the presence of anovulation in PCOS is uncommon, although one report found that among hyperandrogenic women with regular menstrual cycles, the rate of anovulation is 21% (25). Classically, the disorder is lifelong, characterized by abnormal menses from puberty with acne and hirsutism arising in the teens. It may arise in adulthood, concomitant with the emergence of obesity, presumably because this is accompanied by increasing hyperinsulinemia (26).


Gynecology_Novak

Gynecology_Novak. The sonographic criteria for PCO requires the presence of 12 or more follicles in either ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume (>10 mL). A single ovary meeting these criteria is sufficient to affix the PCO diagnosis (19). The appearance of PCO on ultrasound scanning is common. Only a fraction of those with PCO appearance have the clinical and/or endocrine features of PCOS. A PCO appearance is found in about 23% of women of reproductive age, while estimates of the incidence of PCOS vary between 5% and 10% (27). Polycystic appearing ovaries in women with PCOS was not associated with increased cardiovascular disease risk, independent of body mass index (BMI), age, and insulin levels (28). An English study demonstrated that without symptoms of polycystic ovary syndrome, a PCO appearance alone is not associated with impaired fecundity or fertility (29).


Gynecology_Novak

Gynecology_Novak. Obesity occurs in more than 50% of patients with PCOS. The body fat is usually deposited centrally (android obesity), and a higher waist-to-hip ratio is associated with insulin resistance indicating an increased risk of diabetes mellitus and cardiovascular disease (30). Among women with PCOS, there is widespread variability in the degree of adiposity by geographic location and ethnicity. In studies in Spain, China, Italy, and the United States, the percentage of obese women with PCOS were 20%, 43%, 38%, and 69%, respectively (31).


Gynecology_Novak

Gynecology_Novak. Insulin resistance resulting in hyperinsulinemia is commonly exhibited in PCOS. Insulin resistance may eventually lead to the development of hyperglycemia and type 2 diabetes mellitus (32). About one-third of obese PCOS patients have impaired glucose tolerance (IGT), and 7.5% to 10% have type 2 diabetes mellitus (33). These rates are mildly increased in nonobese women who have PCOS (10% IGT; 1.5% diabetes, respectively), compared with the general population of the United States (7.8% IGT; 1% diabetes, respectively) (34,35). Abnormal lipoproteins are common in PCOS and include elevated total cholesterol, triglycerides, and low-density lipoproteins (LDL); and,low levels of high-density lipoproteins (HDL), and apoprotein A-I (30,36). According to one report, the most characteristic lipid alteration is decreased levels of HDL2α (37).


Gynecology_Novak

Gynecology_Novak. Other observations in women with PCOS include impaired fibrinolysis, as shown by elevated circulating levels of plasminogen activator inhibitor, an increased incidence of hypertension over the years (which reaches 40% by perimenopause), a greater prevalence of atherosclerosis and cardiovascular disease, and an estimated sevenfold increased risk for myocardial infarction (36,38–41). Pathology Macroscopically, ovaries in women with PCOS are two to five times the normal size. A cross-section of the surface of the ovary discloses a white, thickened cortex with multiple cysts that are typically less than a centimeter in diameter. Microscopically, the superficial cortex is fibrotic and hypocellular and may contain prominent blood vessels. In addition to smaller atretic follicles, there is an increase in the number of follicles with luteinized theca interna. The stroma may contain luteinized stromal cells (42).


Gynecology_Novak

Gynecology_Novak. The hyperandrogenism and anovulation that accompany PCOS may be caused by abnormalities in four endocrinologically active compartments: (i) the ovaries, (ii) the adrenal glands, (iii) the periphery (fat), and (iv) the hypothalamus–pituitary compartment (Fig. 31.5). In patients with PCOS, the ovarian compartment is the most consistent contributor of androgens. Dysregulation of CYP17, the androgen-forming enzyme in both the adrenals and the ovaries, may be one of the central pathogenetic mechanisms underlying hyperandrogenism in PCOS (43). The ovarian stroma, theca, and granulosa contribute to ovarian hyperandrogenism and are stimulated by LH (44). This hormone relates to ovarian androgenic activity in PCOS in a number of ways. 1. Total and free testosterone levels correlate directly with LH levels (45). 2. The ovaries are more sensitive to gonadotropic stimulation, possibly as a result of CYP17 dysregulation (43). 3.


Gynecology_Novak

Gynecology_Novak. 1. Total and free testosterone levels correlate directly with LH levels (45). 2. The ovaries are more sensitive to gonadotropic stimulation, possibly as a result of CYP17 dysregulation (43). 3. Treatment with a gonadotropin-releasing hormone (GnRH) agonist effectively suppresses serum testosterone and androstenedione levels (46). 4. Larger doses of a GnRH agonist are required for androgen suppression than for endogenous gonadotropin-induced estrogen suppression (47).


Gynecology_Novak

Gynecology_Novak. 4. Larger doses of a GnRH agonist are required for androgen suppression than for endogenous gonadotropin-induced estrogen suppression (47). The increased testosterone levels in patients with PCOS are considered ovarian in origin. The serum total testosterone levels are usually no more than twice the upper normal range (20 to 80 ng/dL). However, in ovarian hyperthecosis, values may reach 200 ng/dL or more (48). The adrenal compartment plays a role in the development of PCOS. Although the hyperfunctioning CYP17 androgen-forming enzyme coexists in both the ovaries and the adrenal glands, DHEAS is increased in only about 50% of patients with PCOS (49,50). The hyperresponsiveness of DHEAS to stimulation with ACTH, the onset of symptoms around puberty, and the observation of 17,20-lyase activation (one of the two CYP17 enzymes) are key events in adrenarche that led to the hypothesis that PCOS arises as an exaggeration of adrenarche (48).


Gynecology_Novak

Gynecology_Novak. The peripheral compartment, defined as the skin and the adipose tissue, manifests its contribution to the development of PCOS in several ways. 1. The presence and activity of 5α-reductase in the skin largely determines the presence or absence of hirsutism (22,23). 2. Aromatase and 17β-hydroxysteroid dehydrogenase activities are increased in fat cells and peripheral aromatization is increased with increased body weight (51,52).


Gynecology_Novak

Gynecology_Novak. 2. Aromatase and 17β-hydroxysteroid dehydrogenase activities are increased in fat cells and peripheral aromatization is increased with increased body weight (51,52). Figure 31.5 Pathophysiological characteristics of the polycystic ovary syndrome (PCOS). Insulin resistance results in a compensatory hyperinsulinemia, which stimulates ovarian androgen production in an ovary genetically predisposed to PCOS. Arrest of follicular development (red “X”) and anovulation could be caused by the abnormal secretion of gonadotropins such as follicle-stimulating hormone (FSH) or luteinizing hormone (LH) (perhaps induced by hyperinsulinemia), intraovarian androgen excess, direct effects of insulin, or a combination of these factors. Insulin resistance, in concert with genetic factors, may also lead to hyperglycemia and an adverse profile of cardiovascular risk factors. (From Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med 2005;353:2578–2588, with permission.) 3.


Gynecology_Novak

Gynecology_Novak. With obesity the metabolism of estrogens, by way of reduced 2-hydroxylation and 17α-oxidation, is decreased and metabolism via estrogen active 16-hydroxyestrogens (estriol) is increased (53). 4. Whereas estradiol (E2) is at a follicular phase level in patients with PCOS, estrone (E1) levels are increased as a result of peripheral aromatization of androstenedione (54). 5. A chronic hyperestrogenic state, with reversal of the E1-to-E2 ratio, results and is unopposed by progesterone. The hypothalamic–pituitary compartment participates in aspects critical to the development of PCOS. 1. An increase in LH pulse frequency relative to those in the normal follicular phase is the result of increased GnRH pulse frequency (55). 2. This increase in LH pulse frequency explains the frequent observation of an elevated LH and LH-to-FSH ratio. 3.


Gynecology_Novak

Gynecology_Novak. 2. This increase in LH pulse frequency explains the frequent observation of an elevated LH and LH-to-FSH ratio. 3. FSH is not increased with LH, likely because of the combination of increased gonadotropin pulse frequency and the synergistic negative feedback of chronically elevated estrogen levels and normal follicular inhibin. 4. About 25% of patients with PCOS exhibit mildly elevated prolactin levels, which may result from abnormal estrogen feedback to the pituitary gland. In some patients with PCOS, bromocriptine has reduced LH levels and restored ovulatory function (56).


Gynecology_Novak

Gynecology_Novak. Polycystic ovary syndrome is a complex multigenetic disorder that results from the interaction between multiple genetic and environmental factors. Genetic studies of PCOS reported allele sharing in large PCOS patient populations and linkage studies focused on candidate genes most likely to be involved in the pathogenesis of PCOS. These genes can be grouped in four categories: (i) insulin resistance–related genes, (ii) genes that interfere with the biosynthesis and the action of androgens, (iii) genes that encode inﬂammatory cytokines, and (iv) other candidate genes (57).


Gynecology_Novak

Gynecology_Novak. Linkage studies identified the follistatin, CYP11A, Calpain 10, IRS-1 and IRS-2 regions and loci near the insulin receptor (19p13.3), SHBG, TCF7L2, and the insulin genes, as likely PCOS candidate genes (58–64). A polymorphic variant, D19S884, in FBN3 was found to be associated with risk of PCOS (65). Using theca cells derived from women with PCOS elevated mRNA levels was noted for CYP11A, 3BHSD2, and CYP17 genes with corresponding overproduction of testosterone, 17-α-hydroxyprogesterone, and progesterone. Despite the characteristically heightened steroidogenesis in POCS, the STARB gene was not overexpressed (58). Microarray data using theca cells from PCOS women did not identify any genes near the 19p13.3 locus that were differentially expressed; however, the mRNAs of several genes that map to 19p13.3, including the insulin receptor, p114-Rho-GEF, and several expressed sequence tags, were detected in both PCOS and normal theca cells. Those studies identified new factors that might


Gynecology_Novak

Gynecology_Novak. map to 19p13.3, including the insulin receptor, p114-Rho-GEF, and several expressed sequence tags, were detected in both PCOS and normal theca cells. Those studies identified new factors that might impact theca cell steroidogenesis and function, including cAMP-GEFII, genes involved in all-transretinoic acid (atRA) synthesis signaling, genes that participate in the Wnt signal transduction pathway, and transcription factor GATA6. These findings suggest that a 19p13.3 locus or some other candidate gene may be a signal transduction gene that results in overexpression of a suite of genes downstream that may affect steroidogenic activity (66). Polymorphisms in major folliculogenesis genes, GDF9, BMP15, AMH, and AMHR2, are not associated with PCOS susceptibility (67).


Gynecology_Novak

Gynecology_Novak. Insulin Resistance Patients with PCOS frequently exhibit insulin resistance and hyperinsulinemia. Insulin resistance and hyperinsulinemia participate in the ovarian steroidogenic dysfunction of PCOS. Insulin alters ovarian steroidogenesis independent of gonadotropin secretion in PCOS. Insulin and insulin-like growth factor I (IGF-I) receptors are present in the ovarian stromal cells. A specific defect in the early steps of insulin receptor–mediated signaling (diminished autophosphorylation) was identified in 50% of women with PCOS (68). Insulin has direct and indirect roles in the pathogenesis of hyperandrogenism in PCOS. Insulin in collaboration with LH enhances the androgen production of theca cells. Insulin inhibits the hepatic synthesis of sex hormone–binding globulin, the main circulating protein that binds to testosterone, thus increasing the proportion of unbound or bioavailable testosterone (13).


Gynecology_Novak

Gynecology_Novak. The most common cause of insulin resistance and compensatory hyperinsulinemia is obesity, but despite its frequent occurrence in PCOS, obesity alone does not explain this important association (56). The insulin resistance associated with PCOS is not solely the result of hyperandrogenism based on the following: 1. Hyperinsulinemia is not a characteristic of hyperandrogenism in general but is uniquely associated with PCOS (69). 2. In obese women with PCOS, 30% to 45% have glucose intolerance or frank diabetes mellitus, whereas ovulatory hyperandrogenic women have normal insulin levels and glucose tolerance (69). It seems that the associations between PCOS and obesity on the action of insulin are synergistic. 3. Suppression of ovarian steroidogenesis in women with PCOS with long-acting GnRH analogues does not change insulin levels or insulin resistance (70). 4.


Gynecology_Novak

Gynecology_Novak. 3. Suppression of ovarian steroidogenesis in women with PCOS with long-acting GnRH analogues does not change insulin levels or insulin resistance (70). 4. Oophorectomy in patients with hyperthecosis accompanied by hyperinsulinemia and hyperandrogenemia does not change insulin resistance, despite a decrease in androgen levels (70,71).


Gynecology_Novak

Gynecology_Novak. 4. Oophorectomy in patients with hyperthecosis accompanied by hyperinsulinemia and hyperandrogenemia does not change insulin resistance, despite a decrease in androgen levels (70,71). Acanthosis nigricans is a reliable marker of insulin resistance in hirsute women. This thickened, pigmented, velvety skin lesion is most often found in the vulva and may be present on the axilla, over the nape of the neck, below the breast, and on the inner thigh (72). The HAIR-AN syndrome consists of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) (68,73). These patients often have high testosterone levels (>150 ng/dL), fasting insulin levels of greater than 25 μIU/mL (normal <20 to 24 μIU/mL), and maximal serum insulin responses to glucose load (75 gm) exceeding 300 μIU/mL (normal is <160 μIU/m: at 2 hours postglucose load).


Gynecology_Novak

Gynecology_Novak. The 2003 Rotterdam Consensus Group recommends that obese women with PCOS and nonobese PCOS patients with risk factors for insulin resistance, such as a family history of diabetes, should be screened for metabolic syndrome, including glucose intolerance with an oral glucose tolerance test (19). The standard 2-hour oral glucose tolerance test (OGTT) provides an assessment of both the degrees of hyperinsulinemia and glucose tolerance and yields the highest amount of information for a reasonable cost and risk (7).


Gynecology_Novak

Gynecology_Novak. Multiple other testing or screening schema were proposed to assess the presence of hyperinsulinemia and insulin resistance. In one, the fasting glucose-to-insulin ratio is determined, and values less than 4.5 indicate insulin resistance. Using the 2-hour GTT with insulin levels, 10% of nonobese and 40% to 50% of obese PCOS women have impaired glucose tolerance (IGT = 2-hour glucose level ≥140 but ≤199 mg/dL) or overt type 2 diabetes mellitus (any glucose level >200 mg/dL). Some research studies utilized a peak insulin level of over 150 μIU/mL or a mean level of over 84 μIU/mL over the three blood draws of a 2-hour GTT as a criteria to diagnoses hyperinsulinemia.


Gynecology_Novak

Gynecology_Novak. The documentation of hyperinsulinemia using either the glucose to insulin ratio or the 2-hour GTT with insulin is problematic. When compared to the gold standard measure for insulin resistance, the hyperinsulemic-euglycemic clamp, it shows that the glucose-to-insulin ratio does not always accurately portray insulin resistance. When hyperglycemia is present, a relative insulin secretion deficit is present. This deficient insulin secretion exacerbates the effects of insulin resistance and renders inaccurate the use of hyperinsulinemia as an index of insulin resistance. Thus, routine measurements of insulin levels may not be particularly useful.


Gynecology_Novak

Gynecology_Novak. Although detection of insulin resistance, per se, is not of practical importance to the diagnosis or management of PCOS, testing women with PCOS for glucose intolerance is of value because their risk of cardiovascular disease correlates with this finding. An appropriate frequency for such screening depends on age, BMI and waist circumference, all of which increase risk. Two-Hour Glucose Tolerance Test Normal Glucose Ranges (World Health Organization criteria, after 75-gm glucose load) Fasting 64 to 128 mg/dL One hour 120 to 170 mg/dL Two hour 70 to 140 mg/dL Two-Hour Glucose Values for Impaired Glucose Tolerance and Type 2 Diabetes (World Health Organization criteria, after 75-gm glucose load) Impaired (2-hour) = 140 to 199 mg/dL


Gynecology_Novak

Gynecology_Novak. Two-Hour Glucose Values for Impaired Glucose Tolerance and Type 2 Diabetes (World Health Organization criteria, after 75-gm glucose load) Impaired (2-hour) = 140 to 199 mg/dL Abnormal glucose metabolism may be significantly improved with weight reduction, which may reduce hyperandrogenism and restore ovulatory function (74). In obese, insulin-resistant women, caloric restriction that results in weight reduction will reduce the severity of insulin resistance (a 40% decrease in insulin level with a 10-kg weight loss) (75). This decrease in insulin levels should result in a marked decrease in androgen production (a 35% decrease in testosterone levels with a 10-kg weight loss) (76). Exercise reduces insulin resistance, independent from any associated weight loss, but data on the impact of exercise on the principal manifestations of PCOS are lacking.


Gynecology_Novak

Gynecology_Novak. In addition to addressing the increased risk for diabetes, the clinician should recognize insulin resistance or hyperinsulinemia as a cluster syndrome called metabolic syndrome or dysmetabolic syndrome X. Recognition of the importance of insulin resistance or hyperinsulinemia as a risk factor for cardiovascular disease led to diagnostic criteria for the dysmetabolic syndrome. The more dysmetabolic syndrome X criteria are present, the higher the level of insulin resistance and its downstream consequences. The presence of three of the following five criteria confirm the diagnosis, and an insulin-lowering agent and/or other interventions may be warranted (19). Fasting glucose: 110–126 mg/dL Two-hour glucose (75 gm OGTT): 140–199 mg/dL


Gynecology_Novak

Gynecology_Novak. Fasting glucose: 110–126 mg/dL Two-hour glucose (75 gm OGTT): 140–199 mg/dL Risk factors for the dysmetabolic syndrome include nonwhite race, sedentary lifestyle, BMI greater than 25, age over 40 years, cardiovascular disease, hypertension, PCOS, hyperandrogenemia, insulin resistance, HAIR-AN syndrome, nonalcoholic steatohepatitis (NASH), and a family history of type 2 diabetes mellitus, gestational diabetes, or impaired glucose tolerance. Comprehensive treatment of PCOS addresses reproductive, metabolic and psychological features.


Gynecology_Novak

Gynecology_Novak. A report by the Androgen Excess and PCOS Society concluded that lifestyle management, either alone or combined with antiobesity pharmacologic and/or surgical treatments, should be used as the primary therapy in overweight and obese women with PCOS (31). Lifestyle management of obesity in PCOS is multifactorial. Dietary management of obesity should focus on reducing body weight, maintaining a lower long-term body weight, and preventing weight gain. An initial weight loss of greater than or equal to 5% to 10% is recommended. In obese and overweight women with PCOS, dietary interventions with a resultant weight reduction of more than 5% to less than 15% over the starting body weight is associated with a reduction in either total or free testosterone, adrenal androgens, and improvement in SHBG levels. Metabolic improvements in fasting insulin, glucose, glucose tolerance, total cholesterol, triglycerides, plasminogen activator inhibitor-1, and free fatty acids are reported. Clinically,


Gynecology_Novak

Gynecology_Novak. SHBG levels. Metabolic improvements in fasting insulin, glucose, glucose tolerance, total cholesterol, triglycerides, plasminogen activator inhibitor-1, and free fatty acids are reported. Clinically, hirsutism, menstrual function, and ovulation are all improved (31).


Gynecology_Novak

Gynecology_Novak. Structured exercise improves insulin resistance and offers significant benefits in PCOS. The incorporation of structured exercise, behavior modification, and stress management strategies Table 31.5 Lifestyle Modification Principles Suggested for Obesity Management in Polycystic Ovary Syndrome (PCOS) 1. Lifestyle modification is the first form of therapy, combining behavioral (reduction of psychosocial stressors), dietary, and exercise management. 2. Reduced-energy diets (500–1,000 kcal/day reduction) are effective options for weight loss and can reduce body weight by 7% to 10% over a period of 6 to 12 months. 3. Dietary plans should be nutritionally complete and appropriate for life stage and should aim for <30% of calories from fat, <10% of calories from saturated fat, with increased consumption of fiber, whole-grain breads and cereals, and fruit and vegetables. 4.


Gynecology_Novak

Gynecology_Novak. 4. Alternative dietary options (increasing dietary protein, reducing glycemic index, reducing carbohydrate) may be successful for achieving and sustaining a reduced weight but more research is needed in PCOS specifically. 5. The structure and support within a weight-management program is crucial and may be more important than the dietary composition. Individualization of the program, intensive follow-up and monitoring by a physician, and support from the physician, family, spouse, and peers will improve retention. 6. Structured exercise is an important component of a weight-loss regime; aim for >30 min/day. Reprinted with permission from Moran LJ, Pasquali R, Teede HJ, et al. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 2009;92:1966–1982. as fundamental components of lifestyle management increases the success of the weight loss strategy (Table 31.5).


Gynecology_Novak

Gynecology_Novak. as fundamental components of lifestyle management increases the success of the weight loss strategy (Table 31.5). Even though lifestyle management strategies should be used as the primary therapy in obese and overweight women with PCOS, they are difficult to maintain long term. Alternative approaches to the treatment of obesity include the use of pharmacologic agents, such as orlistat, sibutramine, and rimonabant, or bariatric surgery (31). The NIH clinical recommendations advise bariatric surgery when BMI is greater than 40 kg/m2 or greater than 35 kg/m2 in patients with a high-risk, obesity-related condition after failure of other treatments for weight control (31,77).


Gynecology_Novak

Gynecology_Novak. Dyslipidemia is one of the most common metabolic disorders seen in PCOS patients (up to 70% prevalence in a US PCOS population) (78). It is associated with insulin resistance and hyperandrogenism in combination with environmental (diet, physical exercise) and genetic factors. Various abnormal patterns include decreased levels of HDL, elevated levels of triglycerides, decreased total and LDL levels, and altered LDL quality (79,80). To assess cardiovascular risks and prevent disease in patients with PCOS, the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society recommend the following monitoring activities (80): 1. Waist circumference and BMI measurement at every visit, using the National Health and Nutrition Examination Survey method. 2. A complete lipid profile based using the American Heart Association guidelines (Fig. 31.6). If the fasting serum lipid profile is normal, it should be reassessed every 2 years or sooner if weight gain occurs. 3.


Gynecology_Novak

Gynecology_Novak. 3. A 2-hour post-75-g oral glucose challenge measurement in PCOS women with a BMI greater than 30 kg/m2, or alternatively in lean PCOS women with advanced age (40 years), personal history of gestational diabetes, or family history of type 2 diabetes. 4. Blood pressure measurement at each visit. The ideal blood pressure is 120/80 or lower. Prehypertension should be treated because blood pressure control has the largest benefit in reducing cardiovascular diseases. 5. Regular assessment for depression, anxiety, and quality of life. 130 100 70 160 130 100 LDL target values, mg/dL Non-HDL target values, mg/dL PCOS PCOS with metabolic PCOS with metabolic syndrome syndrome and Type 2 diabetes mellitus, overt vascular and/or renal disease


Gynecology_Novak

Gynecology_Novak. PCOS PCOS with metabolic PCOS with metabolic syndrome syndrome and Type 2 diabetes mellitus, overt vascular and/or renal disease Figure 31.6 Lipid guidelines in PCOS to prevent cardiovascular disease risk (values in mg/dL). (Non-HDL = Total Cholesterol − HDL, if TG <400 mg/dL). (Data for figure derived from Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab 2010;95(5):2038–2049.) A significant proportion of the population and particularly the obese population have inadequate vitamin D levels. Because vitamin D plays a role in many metabolic activities, assessment and supplementation when indicated are recommended. Deficient: 8 ng/mL or less (≤20 nmol/L) Insufficient: 8–20 ng/mL (20–50 nmol/L)


Gynecology_Novak

Gynecology_Novak. Deficient: 8 ng/mL or less (≤20 nmol/L) Insufficient: 8–20 ng/mL (20–50 nmol/L) Optimal: 20–60 ng/mL (50–150 nmol/L; 40–50 ng/mL is treatment goal) High: 60–90 ng/mL (150–225 nmol/L) Toxic: >90 ng/mL or greater (≥225 nmol/L) 1. The body uses 3,000 to 5,000 IU D3 per day. 2. In the absence of the sun, 600 IU of D3 are required to maintain vitamin D levels. 3. D2 is more rapidly metabolized and is less potent than D3. 4. Patients receiving 50,000 IU of vitamin D2 once a week for 8 weeks will usually correct a vitamin D deficiency, and this can be followed by giving 50,000 U of vitamin D2 once every other week to maintain vitamin D sufficiency. 5. D3 is more potent and appropriate dosing to correct levels is still under investigation.


Gynecology_Novak

Gynecology_Novak. 5. D3 is more potent and appropriate dosing to correct levels is still under investigation. In chronic anovulatory patients with PCOS, persistently elevated estrogen levels, which are uninterrupted by progesterone, increase the risk of endometrial carcinoma (81,82). These endometrial cancers are usually well differentiated, stage I lesions with a cure rate of more than 90% (see Chapter 35). Endometrial biopsy should be considered in PCOS patients, because they may occasionally harbor these cancers as early as the third decade of life. Abnormal bleeding, increasing weight, and age are factors that should lower the threshold for endometrial sampling. Prevention of endometrial cancer is a core management goal for patients with Treatment of Hyperandrogenism and PCOS


Gynecology_Novak

Gynecology_Novak. Treatment of Hyperandrogenism and PCOS PCOS. If other dimensions of management do not induce regular ovulation (e.g. clomiphene) or impose continuous progestation inﬂuence (e.g., oral contraceptives), regular secrectory transformation and menstruation should be induced with periodic administration of a progestational agent. Even though the hyperestrogenic state is associated with an increased risk of breast cancer, studies examining the relationship between PCOS and breast cancer have not always identified a significantly increased risk (82–86). The risk of ovarian cancer is increased two-to threefold in women with PCOS (82,87). The clinical features of PCOS, such as infertility, acne, hirsutism, and obesity, promote psychological morbidity. Women with PCOS face challenges to their feminine identity that can lead to loss of self-esteem, anxiety, poor body image, and depression (88).


Gynecology_Novak

Gynecology_Novak. A study examining the prevalence of depression and other mood disorders in women with PCOS reported a significantly increased prevalence of depression (35% to 40%) when compared with controls (10.7%), after adjusting for BMI, and a family history of depression and/or infertility. Other mood disorders such as anxiety and eating disorders were common in women with PCOS (89). The high prevalence of depression and other mental health disorders in women with PCOS suggests that assessment and treatment of mental health disorders should be included in the evaluation and management plan (89). Lifestyle management improves quality of life and depression in obese and overweight and women with PCOS (88).


Gynecology_Novak

Gynecology_Novak. Treatment depends on a patient’s goals. Some patients require hormonal contraception, whereas others desire ovulation induction. In all cases where there is significant ovulatory dysfunction, progestational interruption of the unopposed estrogen effects on the endometrium is necessary. This may be accomplished by periodic luteal function resulting from ovulation induction, progestational suppression via contraceptive formulations, or intermittent administration of progestational agents for endometrial or menstrual regulation. Interruption of the steady state of hyperandrogenism and control of hirsutism usually can be accomplished simultaneously. Patients desiring pregnancy are an exception, and for them effective control of hirsutism may not be possible. Treatment regimens for hirsutism are listed in Table 31.6. The induction of ovulation and treatment of infertility are discussed in Chapter 32. Table 31.6 Medical Treatment of Hirsutism


Gynecology_Novak

Gynecology_Novak. Table 31.6 Medical Treatment of Hirsutism Weight Reduction Weight reduction is the initial recommendation for patients with accompanying obesity because it promotes health, reduces insulin, SHBG, and androgen levels, and may restore ovulation either alone or combined with ovulation-induction agents (75). Weight loss of as little as 5% to 7% over a 6-month period can reduce the bioavailable or calculated free testosterone level significantly and restore ovulation and fertility in more than 75% of women (90). Exercise involving large muscle groups reduces insulin resistance and can be an important component of nonpharmacologic, lifestyle-modifying management. Oral Contraceptives Combination oral contraceptives (OCs) decrease adrenal and ovarian androgen production and reduce hair growth in nearly two-thirds of hirsute patients (91–94). Treatment with OCs offers the following benefits: 1. The progestin component suppresses LH, resulting in diminished ovarian androgen production. 2.


Gynecology_Novak

Gynecology_Novak. The progestin component suppresses LH, resulting in diminished ovarian androgen production. 2. The estrogen component increases hepatic production of SHBG, resulting in decreased free testosterone concentration (95,96). 3. Circulating androgen levels are reduced, including those of DHEAS, which to some extent is independent of the effects of both LH and SHBG (30,97). 4. Estrogens decrease conversion of testosterone to DHT in the skin by inhibition of 5α-reductase.


Gynecology_Novak

Gynecology_Novak. 4. Estrogens decrease conversion of testosterone to DHT in the skin by inhibition of 5α-reductase. When an OC is used to treat hirsutism, a balance must be maintained between the decrease in free testosterone levels and the intrinsic androgenicity of the progestin. Three progestin compounds that are present in OCs (norgestrel, norethindrone, and norethindrone acetate) are believed to be androgen dominant. The androgenic bioactivity of these steroids may be a factor of their shared structural similarity with 19-nortestosterone steroids (98). Oral contraceptives containing the so-called new progestins (desogestrel, gestodene, norgestimate, and drospirenone) have minimized androgenic activity. However, there is limited evidence of clinically measurable differences in outcome resulting from the disparity of in vitro estimates of androgenic potency.


Gynecology_Novak

Gynecology_Novak. The use of OCs alone may be relatively ineffective (<10% success rate) in the treatment of hirsutism in women with PCOS, and the OCs may exacerbate insulin resistance in these patients (99,100). Effective protocols for pharmacologic management of significant hirsutism with OCs usually include coadministration of agents that impede androgen action.


Gynecology_Novak

Gynecology_Novak. Oral or intramuscular administration of medroxyprogesterone acetate (MPA) successfully treats hirsutism (101). It directly affects the hypothalamic–pituitary axis by decreasing GnRH production and the release of gonadotropins, thereby reducing testosterone and estrogen production by the ovary. Despite a decrease in SHBG, total and free androgen levels are decreased significantly (102). The recommended oral dose for GnRH suppression is 20 to 40 mg daily in divided dosages or 150 mg given intramuscularly every 6 weeks to 3 months in the depot form. Hair growth is reduced in up to 95% of patients (103). Side effects of the treatment include amenorrhea, bone mineral density loss, depression, ﬂuid retention, headaches, hepatic dysfunction, and weight gain. MPA is not commonly used for hirsutism.


Gynecology_Novak

Gynecology_Novak. Administration of GnRH agonists may allow the differentiation of androgen produced by adrenal sources from that of ovarian sources (47). It was shown to suppress ovarian steroids to castrate levels in patients with PCOS (104). Treatment with leuprolide acetate given intramuscularly every 28 days decreases hirsutism and hair diameter in both idiopathic hirsutism and hirsutism secondary to PCOS (105). Ovarian androgen levels are significantly and selectively suppressed. The addition of OC or estrogen replacement therapy to GnRH agonist treatment (addback therapy) prevents bone loss and other side effects of menopause, such as hot ﬂushes and genital atrophy. The hirsutism-reducing effect is retained (102,106). Suppression of hirsutism is not potentiated by the addition of estrogen replacement therapy to GnRH agonist treatment (107).


Gynecology_Novak

Gynecology_Novak. than 0.5 mg every evening should be avoided to prevent the risk of adrenal suppression and severe side effects that resemble Cushing syndrome. To avoid oversuppression of the pituitary– adrenal axis, morning serum cortisol levels should be monitored intermittently (maintain at >2 μg/dL). Reduction in hair growth rate was reported, and significant improvement in acne associated with adrenal hyperandrogenism (108). Ketoconazole Ketoconazole inhibits the key steroidogenic cytochromes. Administered at a low dose (200 mg per day), it can significantly reduce the levels of androstenedione, testosterone, and calculated free testosterone (109). It is rarely used for the chronic inhibition of androgen production in women with hyperandrogenism because of the serious risk of adrenocortical suppression and development of adrenal crisis (15).


Gynecology_Novak

Gynecology_Novak. Spironolactone Spironolactone is a specific antagonist of aldosterone, which competitively binds to the aldosterone receptors in the distal tubular region of the kidney. It is an effective potassium-sparing diuretic that originally was used to treat hypertension. The effectiveness of spironolactone in the treatment of hirsutism is based on the following mechanisms: 1. Competitive inhibition of DHT at the intracellular receptor level (22). 2. Suppression of testosterone biosynthesis by a decrease in the CYP enzymes (110). 3. Increase in androgen catabolism (with increased peripheral conversion of testosterone to estrone). 4. Inhibition of skin 5α-reductase activity (22).


Gynecology_Novak

Gynecology_Novak. 3. Increase in androgen catabolism (with increased peripheral conversion of testosterone to estrone). 4. Inhibition of skin 5α-reductase activity (22). Although total and free testosterone levels are reduced significantly in patients with both PCOS and idiopathic hirsutism (hyperandrogenism with regular menses) after treatment with spironolactone, total and free testosterone levels in patients with PCOS remain higher than those with idiopathic hirsutism (hyperandrogenism with regular menses) (111). In both groups, SHBG levels are unaltered. The reduction in circulating androgen levels observed within a few days of spironolactone treatment partially accounts for the progressive regression of hirsutism.


Gynecology_Novak

Gynecology_Novak. At least a modest improvement in hirsutism can be anticipated in 70% to 80% of women using at least 100 mg of spironolactone per day for 6 months (112). Spironolactone reduces the daily linear growth rate of sexual hair, hair shaft diameters, and daily hair volume production (113). Combination therapy with spironolactone and oral contraceptives seems effective via their differing but synergistic activities (15,114). The most common dose is 50 to 100 mg twice daily. Women treated with 200 mg per day show a greater reduction in hair shaft diameter than women receiving 100 mg per day (115). Maximal inhibition of hirsutism is noted between 3 and 6 months but continues for 12 months. Electrolysis can be recommended 9 to 12 months after the initiation of spironolactone for permanent hair removal.


Gynecology_Novak

Gynecology_Novak. The most common side effect of spironolactone is menstrual irregularity (usually metrorrhagia), which may occur in over 50% of patients with a dosage of 200 mg per day (115). Normal menses may resume with reduction of the dosage. Infrequently, other side effects such as mastodynia, urticaria, or scalp hair loss may occur. Nausea and fatigue can occur with high doses (112). Because spironolactone can increase serum potassium levels, its use is not recommended in patients with renal insufficiency or hyperkalemia. Periodic monitoring of potassium and creatinine levels is suggested. Return of normal menses in amenorrheic patients is reported in up to 60% of cases (111). Patients must be counseled to use contraception while taking spironolactone because it theoretically can feminize a male fetus.


Gynecology_Novak

Gynecology_Novak. Cyproterone Acetate Cyproterone acetate is a synthetic progestin derived from 17-OHP, which has potent antiandrogenic properties. The primary mechanism of cyproterone acetate is competitive inhibition of testosterone and DHT at the level of the androgen receptor (116). This agent induces hepatic enzymes and may increase the metabolic clearance rate of plasma androgens (117).


Gynecology_Novak

Gynecology_Novak. A European formulation of ethinyl estradiol with cyproterone acetate significantly reduces plasma testosterone and androstenedione levels, suppresses gonadotropins, and increases SHBG levels (118). Cyproterone acetate shows mild glucocorticoid activity (and may reduce DHEAS levels) (116,119). Administered in a reverse sequential regimen (cyproterone acetate 100 mg per day on days 5 to 15, and ethinyl estradiol 30 to 50 mg per day on cycle days 5 to 26), this cyclic schedule allows regular menstrual bleeding, provides excellent contraception, and is effective in the treatment of even severe hirsutism and acne (120). Side effects of cyproterone acetate include fatigue, weight gain, decreased libido, irregular bleeding, nausea, and headaches. These symptoms occur less often when ethinyl estradiol is added. Cyproterone acetate administration is associated with liver tumors in beagles and is not approved by the U.S. Food and Drug Administration (FDA) for use in the United States.


Gynecology_Novak

Gynecology_Novak. Flutamide Flutamide, a pure nonsteroidal antiandrogen, is approved for treatment of advanced prostate cancer. Its mechanism of action is inhibition of nuclear binding of androgens in target tissues. Although it has a weaker affinity to the androgen receptor than spironolactone or cyproterone acetate, larger doses (250 mg given two or three times daily) may compensate for the reduced potency. Flutamide is a weak inhibitor of testosterone biosynthesis.


Gynecology_Novak

Gynecology_Novak. In a single, 3-month study of ﬂutamide alone, most patients demonstrated significant improvement in hirsutism with no change in androgen levels (121). Significant improvement in hirsutism with a significant drop in androstenedione, DHT, LH, and FSH levels was observed in an 8-month follow-up of ﬂutamide and low-dose OCs in women who did not respond to OCs alone (122). The side effects of ﬂutamide treatment combined with a low-dose OC included dry skin, hot ﬂashes, increased appetite, headaches, fatigue, nausea, dizziness, decreased libido, liver toxicity, and breast tenderness (123).


Gynecology_Novak

Gynecology_Novak. In hyperinsulinemic hyperandrogenemic nonobese PCOS adolescents on a combination of metformin (850 mg per day) and ﬂutamide (62.5 mg per day), the low-dose OC containing drospirenone resulted in a more effective and more efficient reduction in total and abdominal fat excess than was demonstrated by those utilizing an OC with gestodene as the progestin (124). The combination of ethinyl-drospirenone, metformin, and ﬂutamide is effective in reducing excess total and abdominal fat and attenuating dysadipocytokinemia in young women with hyperinsulinemic PCOS. The use of the antiandrogen ﬂutamide appeared to emphasize effects (125). Many patients taking ﬂutamide (50% to 75%) report dry skin, blue-green discoloration of urine, and liver enzyme elevation. Liver toxicity or failure and death are rare but severe side effects of ﬂutamide appear to be dose related (126). The 2008 Endocrine Society clinical practice guidelines do not recommend using ﬂutamide as first-line therapy for treating


Gynecology_Novak

Gynecology_Novak. rare but severe side effects of ﬂutamide appear to be dose related (126). The 2008 Endocrine Society clinical practice guidelines do not recommend using ﬂutamide as first-line therapy for treating hirsutism. If it is used, the lowest effective dose should be given, and the patient’s liver function should be monitored closely (4). Flutamide should not be used in women desiring pregnancy.


Gynecology_Novak

Gynecology_Novak. Finasteride Finasteride is a specific inhibitor of type 2 5α-reductase enzyme activity, approved in the United States at a 5-mg dose for the treatment of benign prostatic hyperplasia, and at a 1-mg dose to treat male-pattern baldness. In a study in which finasteride (5 mg daily) was compared with spironolactone (100 mg daily), both drugs resulted in similar significant improvement in hirsutism, despite differing effects on androgen levels (127). Most of the improvement in hirsutism with finasteride occurred after 6 months of therapy with 7.5 mg of finasteride daily (128). The improvement in hirsutism in the presence of rising testosterone levels is convincing evidence that it is the binding of DHT, and not testosterone, to the androgen receptor that is responsible for hair growth. Finasteride does not prevent ovulation or cause menstrual irregularity. The increase in SHBG caused by OCs further decreases free testosterone levels; OCs in combination with finasteride are more effective


Gynecology_Novak

Gynecology_Novak. does not prevent ovulation or cause menstrual irregularity. The increase in SHBG caused by OCs further decreases free testosterone levels; OCs in combination with finasteride are more effective in reducing hirsutism than finasteride alone. As with spironolactone and ﬂutamide, finasteride could theoretically feminize a male fetus; therefore, both of these agents are used only with additional contraception.


Gynecology_Novak

Gynecology_Novak. Ovarian Wedge Resection Bilateral ovarian wedge resection is associated with only a transient reduction in androstenedione levels and a prolonged minimal decrease in plasma testosterone (129,130). In patients with hirsutism and PCOS who had wedge resection, hair growth was reduced by approximately 16% (17,131). Although Stein and Leventhal’s original report cited a pregnancy rate of 85% following wedge resection and maintenance of ovulatory cycles, subsequent reports show lower pregnancy rates and a concerning incidence of periovarian adhesions (17,132). Instances of premature ovarian failure and infertility were reported (133).


Gynecology_Novak

Gynecology_Novak. Laparoscopic ovarian electrocautery is used as an alternative to wedge resection in patients with severe PCOS whose condition is resistant to clomiphene citrate. In a recent series, ovarian drilling was achieved laparoscopically with an insulated electrocautery needle, using 100-W cutting current to assist entry and 40-W coagulating current to treat each microcyst over 2 seconds (8-mm needle in ovary) (134). In each ovary, 10 to 15 punctures were created. This led to spontaneous ovulation in 73% of patients, with 72% conceiving within 2 years. Of those who underwent a follow-up laparoscopy, 11 of 15 were adhesion free. To reduce adhesion formation, a technique that cauterized the ovary in only four points led to a similar pregnancy rate, with a miscarriage rate of 14% (135). Other laparoscopic techniques using laser instead of electrocautery for laparoscopic ovarian drilling were described (136). Most series report a decrease in both androgen and LH concentrations and an increase in


Gynecology_Novak

Gynecology_Novak. techniques using laser instead of electrocautery for laparoscopic ovarian drilling were described (136). Most series report a decrease in both androgen and LH concentrations and an increase in FSH concentrations (137,138). The beneficial endocrinological effects of laparoscopic ovarian drilling and the improvement in hirsutism were sustained for up to 9 years in patients with PCOS (139). Unilateral diathermy results in bilateral ovarian activity (140). Further studies are anticipated to define candidates who may benefit most from such a procedure. The risk of adhesion formation should be discussed with the patient.


Gynecology_Novak

Gynecology_Novak. Physical Methods of Hair Removal Depilatory creams remove hair only temporarily. They break down and dissolve hair by hydrolyzing disulfide bonds. Although depilatories can have a dramatic effect, many women cannot tolerate these irritative chemicals. The topical use of corticosteroid cream may prevent contact dermatitis. Eﬂornithine hydrochloride cream, also known as diﬂuoromethylornithine (DMFO), irreversibly blocks ornithine decarboxylase (ODC), the enzyme in hair follicles that is important in regulating hair growth. It is effective in the treatment of unwanted facial hair (141). Noticeable results take about 6 to 8 weeks of therapy. Treatment must be continued while inhibition of hair growth is desired, and when the cream is discontinued, hair returns to pretreatment levels after about 8 weeks (4).


Gynecology_Novak

Gynecology_Novak. Shaving is effective and, contrary to common belief, it does not change the quality, quantity, or texture of hair. Plucking, if done unevenly and repeatedly, may cause inﬂammation and damage to hair follicles and render them less amenable to electrolysis. Waxing is a grouped method of plucking in which hairs are plucked out from under the skin surface. The results of waxing last longer (up to 6 weeks) than shaving or depilatory creams (142). Bleaching removes the hair pigment through the use of hydrogen peroxide (usually 6% strength), which is sometimes combined with ammonia. Although hair lightens and softens during oxidation, this method is frequently associated with hair discoloration or skin irritation and is not always effective (141).


Gynecology_Novak

Gynecology_Novak. Electrolysis and laser hair removal are the only permanent means recommended for hair removal. Under magnification, a trained technician destroys each hair follicle individually. When a needle is inserted into a hair follicle, galvanic current, electrocautery, or both used in combination (blend) destroy the hair follicle. After the needle is removed, a forceps is used to remove the hair. Hair regrowth ranges from 15% to 50%. Problems with electrolysis include pain, scarring, and pigmentation. Cost can be an obstacle (143). Laser hair removal destroys the hair follicle through photoablation. These methods are most effective after medical therapy arrests further growth. Insulin Sensitizers Because hyperinsulinemia appears to play a role in PCOS-associated anovulation, treatment with insulin sensitizers may shift the endocrine balance toward ovulation and pregnancy, either alone or in combination with other treatment modalities.


Gynecology_Novak

Gynecology_Novak. Metformin (Glucophage) is an oral biguanide antihyperglycemic drug used extensively for non– insulin-dependent diabetes. Metformin is pregnancy category B drug with no known human teratogenic effect. It lowers blood glucose mainly by inhibiting hepatic glucose production and by enhancing peripheral glucose uptake. Metformin enhances insulin sensitivity at the postreceptor level and stimulates insulin-mediated glucose disposal (144).


Gynecology_Novak

Gynecology_Novak. Metformin has been used extensively to treat oligo-ovulatory infertility, insulin resistance, and hyperandrogenism in PCOS patients. Metformin is used to treat PCOS oligo-ovulatory infertility either alone or in combination with dietary restriction, clomiphene, or gonadotropins. In randomized control studies, metformin improves the odds of ovulation in women with PCOS when compared with placebo (145,146). A large multicenter, randomized control trial in women with PCOS concluded that clomiphene is superior to metformin in achieving live births in infertile women with PCOS. When ovulation was used as the outcome, the combination of metformin and clomiphene was superior to either clomiphene alone or metformin alone (147). Multiple births are a complication of clomiphene therapy.


Gynecology_Novak

Gynecology_Novak. The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, bloating, and ﬂatulence. Because the drug caused fatal lactic acidosis in men with diabetes who have renal insufficiency, baseline renal function testing is suggested (148). The drug should not be given to women with elevated serum creatinine levels (144).


Gynecology_Novak

Gynecology_Novak. Concepts regarding the role of obesity and insulin resistance or hyperinsulinemia in PCOS suggest that the primary intervention should be recommending and assisting with weight loss (5% to 10% of body weight). In those with an elevated BMI, orlistat proved helpful in initiating and maintaining weight loss. A percentage of PCOS patients will respond to weight loss alone with spontaneous ovulation. In those who do not respond to weight loss alone or who are unable to lose weight, the sequential addition of clomiphene citrate followed by an insulin sensitizer, followed by the combination of these agents may promote ovulation without resorting to injectable gonadotropins.


Gynecology_Novak

Gynecology_Novak. A prevailing concern over the increased incidence of spontaneous abortions in women with PCOS and the potential reduction afforded by insulin sensitizers suggests that insulin sensitizers may be beneficial in combination with gonadotropin therapy for ovulation induction or in vitro fertilization (149). Women with early pregnancy loss have a low level of insulin-like growth factor (IGF) binding protein-1 (IGFBP-1), and of circulating glycodelin, which has immunomodulatory effects protecting the developing fetus. Use of metformin increased levels of both factors, which might explain early findings suggesting that metformin use may reduce the high spontaneous abortion rates seen among women with PCOS (150).


Gynecology_Novak

Gynecology_Novak. A number of observational studies suggested that metformin reduces the risk of pregnancy loss (151,152). However, there are no adequately designed and sufficiently powered randomized control trials to address this issue. In the prospective randomized pregnancy and PCOS (PPCOS) trial, there was a concerning nonsignificant trend toward a greater rate of miscarriages in the metformin only group (151). This trend was not noted in other trials. There are no conclusive data to support a beneficial effect of metformin on pregnancy loss, and the trend toward a higher miscarriage rate in the PPCOS trial, which used extended release metformin, is of some concern (145,147). The incidence of ovarian hyperstimulation syndrome is reduced with adjuvant metformin in PCOS patients at risk for severe ovarian hyperstimulation syndrome (153).


Gynecology_Novak

Gynecology_Novak. The incidence of ovarian hyperstimulation syndrome is reduced with adjuvant metformin in PCOS patients at risk for severe ovarian hyperstimulation syndrome (153). Cushing Syndrome The adrenal cortex produces three classes of steroid hormones: glucocorticoids, mineralocorticoids, and sex steroids (androgen and estrogen precursors). Hyperfunction of the adrenal gland can produce clinical signs of increased activity of any or all of these hormones. Increased glucocorticoid action results in nitrogen wasting and a catabolic state. This causes muscle weakness, osteoporosis, atrophy of the skin with striae, nonhealing ulcerations and ecchymoses, reduced immune resistance that increases the risk of bacterial and fungal infections, and glucose intolerance resulting from enhanced gluconeogenesis and antagonism to insulin action.


Gynecology_Novak

Gynecology_Novak. Although most patients with Cushing syndrome gain weight, some lose it. Obesity is typically central, with characteristic redistribution of fat over the clavicles around the neck and on the trunk, abdomen, and cheeks. Cortisol excess may lead to insomnia, mood disturbances, depression, and even overt psychosis. With overproduction of sex steroid precursors, women may exhibit hyperandrogenism (hirsutism, acne, oligomenorrhea or amenorrhea, thinning of scalp hair). Masculinization is rare, and its presence suggests an autonomous adrenal origin, most often an adrenal malignancy. With overproduction of mineralocorticoids, patients may manifest arterial hypertension and hypokalemic alkalosis. The associated ﬂuid retention may cause pedal edema (Table 31.7) (154).


Gynecology_Novak

Gynecology_Novak. Characteristic clinical laboratory findings associated with hypercortisolism are confined mainly to a complete blood count showing evidence of granulocytosis and reduced levels of lymphocytes and eosinophils. Increased urinary calcium secretion may be present. Table 31.7 Overlapping Conditions and Clinical Features of Cushing Syndrome Easy bruising Facial plethora Proximal myopathy (or proximal muscle weakness) Striae (especially if reddish purple and >1 cm wide) In children, weight gain with decreasing growth Cushing syndrome features in the general population that are common and/or less discriminatory Features are listed in random order. ∗Cushing’s syndrome is more likely if onset of the feature is at a younger age.


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Gynecology_Novak. Features are listed in random order. ∗Cushing’s syndrome is more likely if onset of the feature is at a younger age. Causes The six recognized noniatrogenic causes of Cushing syndrome can be divided between those that are ACTH dependent and those that are ACTH independent (Table 31.8). The ACTH-dependent causes can result from ACTH secreted by pituitary adenomas or from an ectopic source. The hallmark of ACTH-dependent forms of Cushing syndrome is the presence of normal or high plasma ACTH concentrations with increased cortisol levels. The adrenal glands are hyperplastic bilaterally. Pituitary ACTH-secreting adenoma, or Cushing disease, is the most common cause of endogenous Cushing syndrome (154). These pituitary adenomas are usually microadenomas (<10 mm in diameter) that may be as small as 1 mm. They behave as though they are resistant, to a variable degree, to the feedback effect of cortisol. Like the normal gland, these tumors secrete ACTH in a pulsatile fashion; unlike the


Gynecology_Novak

Gynecology_Novak. Table 31.8 Causes of Cushing Syndrome ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone. ACTH-dependent Cushing syndrome may be caused by pituitary adenoma, basophil hyperplasia, nodular adrenal hyperplasia, or cyclic Cushing syndrome. normal gland, the diurnal pattern of cortisol secretion is lost. Ectopic ACTH syndrome most often is caused by malignant tumors (155). About one-half of these tumors are small-cell carcinomas of the lung (156). Other tumors include bronchial and thymic carcinomas, carcinoid tumors of the pancreas, and medullary carcinoma of the thyroid. Ectopic corticotropin-releasing hormone (CRH) tumors are rare and include such tumors as bronchial carcinoids, medullary thyroid carcinoma, and metastatic prostatic carcinoma (156). The presence of an ectopic CRH-secreting tumor should be suspected in patients whose dynamic testing suggests pituitary ACTH-dependent disease but who have rapid disease progression and very high plasma ACTH levels.


Gynecology_Novak

Gynecology_Novak. The most common cause of ACTH-independent Cushing syndrome is exogenous or iatrogenic (i.e., superphysiologic therapy with corticosteroids) or factitious (self-induced). Corticosteroids are used in pharmacologic quantities to treat a variety of diseases with an inﬂammatory component. Over time, such therapy will result in Cushing syndrome. When corticosteroids are taken by the patient but not prescribed by a physician, the diagnosis may be especially challenging. The diagnostic workup for Cushing syndrome focuses on the ability to suppress autonomous cortisol secretion and whether ACTH is elevated or suppressed. According to the 2008 Endocrine Society’s clinical practice guidelines for the diagnosis of Cushing syndrome, the initial use of one test with high diagnostic accuracy (24-hour urine free cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-hour dexamethasone suppression test) is recommended. The 24-hour urine-free cortisol (UFC) should be used to diagnose Cushing


Gynecology_Novak

Gynecology_Novak. free cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-hour dexamethasone suppression test) is recommended. The 24-hour urine-free cortisol (UFC) should be used to diagnose Cushing syndrome in pregnant women and in patients with epilepsy, whereas the 1-mg overnight dexamethasone suppression test, rather than UFC, should be used for initial testing for Cushing syndrome in patients with severe renal failure and adrenal incidentaloma. The 2-mg 48-hour dexamethasone suppression test is the optimal test in conditions that are associated with overactivation of the hypothalamic–pituitary–adrenal (HPA) axis: depression, morbid obesity, alcoholism, and diabetes mellitus.


Gynecology_Novak

Gynecology_Novak. Patients with an abnormal result should see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone CRH test. These guidelines are summarized in (Fig. 31.7) (154). Evaluation of suspected Cushing Syndrome Hirsutism, moon facies, striae, dorsocervical/supraclavicular fat pads,proximal muscle weakness, with no exogenous glucocorticoid use Endocrine consult exclude physiologic causes of hypercortisolism re-perform 1 or 2 of studies above,additional testing as needed Overnight dexamethasone suppression 1 mg Late night salivary cortisol (≥≥2 tests) 24 hr Urinary free cortisol


Gynecology_Novak

Gynecology_Novak. Figure 31.7 Algorithm for testing patients suspected of having Cushing syndrome (CS). Diagnostic criteria that suggest Cushing syndrome are a urinary-free cortisol (UFC) greater than the normal range for the assay, serum cortisol greater than 1.8 μg/dL (50 nmol/L) after 1 mg dexamethasone (1 mg DST), and a late night salivary cortisol greater than 145 ng/dL (4 nmol/L). (Based on recommendations from Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526–1540.) Treatment of ACTH-independent Forms of Cushing Syndrome


Gynecology_Novak

Gynecology_Novak. Treatment of ACTH-independent Forms of Cushing Syndrome Excluding cases that are of iatrogenic or factitious etiology, ACTH-independent forms of Cushing syndrome are adrenal in origin. Adrenal cancers are usually very large by the time Cushing syndrome is manifest. This is because the tumors are relatively inefficient synthesizers of steroid hormones. Tumors are larger than 6 cm in diameter and are easily detectable by computed tomography (CT) scanning or magnetic resonance imaging (MRI). Adrenal cancers often produce steroids other than cortisol. Thus, when Cushing syndrome is accompanied by hirsutism or virilization in women or feminization in men, adrenal cancer should be suspected.


Gynecology_Novak

Gynecology_Novak. An adrenal tumor that appears large and irregular on radiologic imaging is suggestive of carcinoma. In these cases, a unilateral adrenalectomy through an abdominal exploratory approach is preferable. In most malignant tumors, complete resection is virtually impossible. However, a partial response to postoperative chemotherapy or radiation may be achieved. Most patients with malignancy die within 1 year. When administered immediately after surgery, mitotane (O,P-DDD, an adrenocorticolytic drug) may be of benefit in preventing or delaying recurrent disease (157). Manifestations of Cushing syndrome in these patients are controlled by adrenal enzyme inhibitors.


Gynecology_Novak

Gynecology_Novak. Adrenal adenomas are smaller than carcinomas and average 3 cm in diameter. These tumors are usually unilateral and infrequently associated with other steroid-mediated syndromes. Micronodular adrenal disease is a disorder of children, adolescents, and young adults. The adrenal glands contain numerous small (>3 mm) nodules, which often are pigmented and secrete sufficient cortisol to suppress pituitary ACTH. This condition can be sporadic or familial. Surgical removal of a neoplasm is the treatment of choice (158,159). If a unilateral, well-circumscribed adenoma is identified by MRI or CT scanning, the ﬂank approach may be the most convenient. The cure rate following surgical removal of adrenal adenomas approaches 100%. Because normal function of the HPA axis is suppressed by autonomous cortisol production, cortisol replacement follows surgery and is titrated downward over several months, during which recovery of normal adrenal function is monitored. Treatment of Cushing Disease


Gynecology_Novak

Gynecology_Novak. Treatment of Cushing Disease The main goals of treatment in ACTH-dependent Cushing syndrome are reversal of clinical features, normalization of biochemical changes with minimal morbidity, and long-term control without recurrence (155). The treatment of choice for Cushing disease is transsphenoidal resection. The remission rate is approximately 70% to 90% and the recurrence rate is 5% to 10% at 5 years and 10% to 20% at 10 years in patients with microadenomas who undergo surgery by an experienced surgeon (160– 164). Patients with macroadenoma have lower remission rates (<60%) and higher recurrence rates (12% to 45%) (165–167). Following surgery, transient diabetes insipidus and enduring compromise of anterior pituitary secretion of growth hormone, gonadotropins, and TSH are common (167,168).


Gynecology_Novak

Gynecology_Novak. Fractionated external beam radiotherapy or stereotactic radiosurgery is used to treat patients with Cushing disease in whom transsphenoidal microsurgery was not successful or in patients who are poor surgical candidates. This therapy can achieve control of hypercortisolemia in approximately 50% to 60% of patients within 3 to 5 years (155,169,170). Hypopituitarism is the most common side effect of pituitary irradiation, and long-term follow-up is essential to detect relapse, which can occur after an initial response to radiotherapy. High-voltage external pituitary radiation (4,200 to 4,500 cGy) is given at a rate not exceeding 200 cGy per day. Only 15% to 25% of adults show total improvement, but approximately 80% of children respond (168,171).


Gynecology_Novak

Gynecology_Novak. Mitotane can be used to induce medical adrenalectomy during or after pituitary radiation (157). The role of medical therapy is to prepare the severely ill patient for surgery and to maintain normal cortisol levels while a patient awaits the full effect of radiation. Occasionally, medical therapy is used for patients who respond to therapy with only partial remission. Adrenal enzyme inhibitors include aminoglutethimide, metyrapone, trilostane, and etomidate. A combination of aminoglutethimide and metyrapone may cause a total adrenal enzyme block, requiring corticosteroid-replacement therapy. Ketoconazole, an FDA-approved antifungal agent, inhibits adrenal steroid biosynthesis at the side arm cleavage and 11β-hydroxylation steps. The dose of ketoconazole for adrenal suppression is 600 to 800 mg per day for 3 months to 1 year (172). Ketoconazole is effective for long-term control of hypercortisolism of either pituitary or adrenal origin.


Gynecology_Novak

Gynecology_Novak. Nelson syndrome results from adenomatous progression of ACTH-secreting cells in patients with Cushing syndrome treated by bilateral adrenalectomy. The macroadenoma that causes this syndrome produces sellar pressure symptoms of headaches, visual field disturbances, and ophthalmoplegia. Extremely high ACTH levels in Nelson syndrome are associated with severe hyper-pigmentation (melanocyte-stimulating hormone activity). The treatment is surgical removal or radiation. The offending adenomatous tissue is often resistant to complete surgical removal (173). This syndrome reportedly complicates 10% to 50% of bilateral adrenalectomy cases. Measuring pituitary MRI and ACTH plasma levels at regular intervals after bilateral adrenalectomy will allow detection of the early progression of corticotroph tumors and the possibility of cure by surgery, particularly with microadenomas (155). Nelson syndrome is less common today because bilateral adrenalectomy is less frequently used as initial treatment.


Gynecology_Novak

Gynecology_Novak. CAH is transmitted as an autosomal recessive disorder. Several adrenocortical enzymes necessary for cortisol biosynthesis may be affected. Failure to synthesize the fully functional enzyme has the following effects: 1. A relative decrease in cortisol production. 2. A compensatory increase in ACTH levels. 3. Hyperplasia of the zona reticularis of the adrenal cortex. 4. An accumulation of the precursors of the affected enzyme in the bloodstream.


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Gynecology_Novak. 21-Hydroxylase Deficiency Deficiency of 21-hydroxylase is responsible for over 90% of all cases of adrenal hyperplasia due to adrenal synthetic enzyme deficiency. The disorder produces a spectrum of conditions; CAH, with or without salt wasting, and milder forms that are expressed as hyperandrogenism of pubertal onset (adult onset adrenal hyperplasia, AOAH). Salt-wasting CAH, the most severe form, affects 75% of patients with congenital manifestations during the first 2 weeks of life and results in a life-threatening hypovolemic salt-wasting crisis, accompanied by hyponatremia, hyperkalemia, and acidosis. The salt-wasting form results from a severity of enzyme deficiency sufficient to result in ineffective aldosterone synthesis. With or without salt-wasting and newborn adrenal crisis, the condition is usually diagnosed earlier in affected female newborns than in males as genital virilization (e.g., clitoromegaly, labioscrotal fusion, and abnormal urethral course) is apparent at birth.


Gynecology_Novak

Gynecology_Novak. In simple virilizing CAH, affected patients are diagnosed as virilized newborn females or as rapidly growing masculinized boys at 3 to 7 years of age. Diagnosis is based on basal levels of the substrate for 21-hydroxylase, 17-OHP; in cases of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency and in milder forms of the disorder with manifestations later in life (acquired, late onset, or adult-onset adrenal hyperplasia), diagnosis depends on basal and ACTH-stimulated levels of 17-OHP. Patients with morning follicular phase 17-OHP levels of less than 300 ng/dL (10 nmol/L) are likely unaffected. When levels are greater than 300 ng/dL, but less than 10,000 ng/dL (300 nmol/L), ACTH testing should be performed to distinguish between 21-hydroxylase deficiency and other enzyme defects or to make the diagnosis in borderline cases. Levels greater than 10,000 ng/dL (300 nmol/L) are virtually diagnostic of congenital adrenal hyperplasia.


Gynecology_Novak

Gynecology_Novak. The nonclassic type of 21-hydroxylase deficiency represents partial deficiency in 21hydroxylation, which produces a late-onset, milder hyperandrogenemia. Its occurrence depends on some degree of functional deficit resulting from mutations affecting both alleles for the 21-hydroxylase enzyme. Heterozygote carriers for mutations in the 21-hydroxylase enzyme will demonstrate normal basal and modestly elevated stimulated levels of 17-OHP, but no abnormalities in circulating androgens. Some women with mild gene defects in both alleles demonstrate modest elevations in circulating 17-OHP concentrations, but no clinical symptoms or signs. The hyperandrogenic symptoms of AOAH are mild and typically present at or after puberty. The three phenotypic varieties are (174): 1. Those with ovulatory abnormalities and features consistent with PCOS (39%) 2. Those with hirsutism alone without oligomenorrhea (39%) 3. Those with elevated circulating androgens but without symptoms (cryptic) (22%).


Gynecology_Novak

Gynecology_Novak. Those with hirsutism alone without oligomenorrhea (39%) 3. Those with elevated circulating androgens but without symptoms (cryptic) (22%). Precocious puberty reveals late-onset congenital adrenal hyperplasia in 5% to 20% of cases that mainly are caused by nonclassic 21-hydroxylase deficiency. Measurement of 17-OHP should be performed in patients presenting with precocious puberty, and a subsequent ACTH stimulation test is recommended if basal 17-OHP is greater than 200 ng/dL. The need for screening patients with hirsutism for adult-onset adrenal hyperplasia depends on the patient population. The frequency of some form of the disorder varies by ethnicity and is estimated at 0.1% of the general population, 1% to 2% of Hispanics and Yugoslavs, and 3% to 4% of Ashkenazi Jews (175). Genetics of 21-Hydroxylase Deficiency 1. The 21-hydroxylase gene is located on the short arm of chromosome 6, in the midst of the HLA region. 2.


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Gynecology_Novak. Genetics of 21-Hydroxylase Deficiency 1. The 21-hydroxylase gene is located on the short arm of chromosome 6, in the midst of the HLA region. 2. The 21-hydroxylase gene is now termed CYP21. Its homologue is the pseudogene CYP21P (176). 3. Because CYP21P is a pseudogene, the lack of transcription renders it nonfunctional. The CYP21 is the active gene. 4. The CYP21 gene and the CYP21P pseudogene alternate with two genes called C4B and C4A, both of which encode for the fourth component (C4) of serum complement (176). 5. The close linkage between the 21-hydroxylase genes and HLA alleles allowed the study of 21-hydroxylase inheritance patterns in families through blood HLA typing (e.g., linkage of HLA-B14 was found in Ashkenazi Jews, Hispanics, and Italians) (177).


Gynecology_Novak

Gynecology_Novak. Women with congenital and adult-onset forms of the disorder are at a significant risk for having affected infants, owing to the high frequency of 21-hydroxylase mutations in the general population. This presents an important rationale for screening hyperandrogenic women for this disorder when they anticipate childbearing. In families at risk for CAH and in instances where one partner expresses the congenital or adult onset form of the disease, first-trimester prenatal screening using chorionic villus sampling is advocated (176). The fetal DNA is used for specific amplification of the CYP21 gene using polymerase chain reaction (PCR) amplification (178). When the fetus is at risk for CAH, maternal dexamethasone treatment can suppress the fetal HPA axis and prevent genital virilization in affected females (179). The dose is 20 μg/kg in three divided doses administered as soon as pregnancy is recognized and no later than 9 weeks of gestation. This is done prior to performing chorionic


Gynecology_Novak

Gynecology_Novak. affected females (179). The dose is 20 μg/kg in three divided doses administered as soon as pregnancy is recognized and no later than 9 weeks of gestation. This is done prior to performing chorionic villus sampling or amniocentesis in the second trimester. Dexamethasone crosses the placenta and suppresses ACTH in the fetus. If the fetus is determined to be an unaffected female or a male, treatment is discontinued. If the fetus is an affected female, dexamethasone therapy is continued.


Gynecology_Novak

Gynecology_Novak. The practice of prenatal dexamethasone treatment for women whose fetuses are at risk for CAH is controversial; seven of eight pregnancies will be treated with dexamethasone unnecessarily, albeit brieﬂy, to prevent one case of ambiguous genitalia. The efficacy and safety of prenatal dexamethasone treatment is not established, and long-term follow-up data on the offspring of treated pregnancies are lacking (180). Numerous studies in experimental animal models showed that prenatal dexamethasone exposure could impair somatic growth, brain development, and blood pressure regulation. A human study of 40 fetuses at risk for CAH who were treated prenatally with dexamethasone to prevent virilization of affected females reported long-term effects on neuropsychological functions and scholastic performance (179,181).


Gynecology_Novak

Gynecology_Novak. The 2010 Endocrine Society guidelines conclude that prenatal dexamethasone therapy should be pursued only through institutional review boards’ approved protocols at centers capable of collecting sufficient outcome data (182). In a small percentage of patients with CAH, hypertension, rather than mineralocorticoid deficiency, develops. The hypertension responds to corticosteroid replacement (183–186). Many of these patients have a deficiency in 11β-hydroxylase (184,185). In most populations, 11β-hydroxylase deficiency accounts for 5% to 8% of the cases of CAH, or 1 in 100,000 births (187). A much higher incidence, 1 in 5,000 to 7,000, was described in Moroccan Jewish immigrants (186). Two 11β-hydroxylase isoenzymes are responsible for cortisol and aldosterone synthesis, respectively, CYP11-B1 and CYP11-B2. They are encoded by two genes on the middle of the long arm of chromosome 8 (187–189).


Gynecology_Novak

Gynecology_Novak. Inability to synthesize a fully functional 11β-hydroxylase enzyme causes a decrease in cortisol production, a compensatory increase in ACTH secretion, and increased production of androstenedione, 11-deoxycortisol, 11-deoxycorticosterone, and DHEA. The diagnosis of 11βhydroxylase-deficient late-onset adrenal hyperplasia is determined when 11-deoxycortisol levels are higher than 25 ng/mL 60 minutes after ACTH(1–24) stimulation (190). Patients with 11β-hydroxylase deficiency may present with either a classic pattern of the disorder or symptoms of a mild deficiency. The severe classic form is found in about two-thirds of the patients with mild-to-moderate hypertension during the first years of life.


Gynecology_Novak

Gynecology_Novak. In about one-third of the patients it is associated with left ventricular hypertrophy, with or without retinopathy, and occasionally death is reported from cerebrovascular accident (183). Signs of androgen excess are common in the severe form and are similar to those seen in the 21-hydroxylase deficiency. In the mild, nonclassic form, children have virilization or precocious puberty but not hypertension. Adult women will seek treatment for postpubertal onset of hirsutism, acne, and amenorrhea.


Gynecology_Novak

Gynecology_Novak. Deficiency of 3β-hydroxysteroid dehydrogenase occurs with varying frequency in hirsute patients (191,192). The enzyme is found in both the adrenal glands and ovaries (unlike 21and 11-hydroxylase) and is responsible for transforming -5 steroids into the corresponding -4 compounds, a step integral to the synthesis of glucocorticoids, mineralocorticoids, and testosterone and estradiol. In severe forms, cortisol and mineralocorticoids are deficient. The clinical spectrum of 3β-hydroxysteroid dehydrogenase deficiency ranges from the classic salt wasting, hypogonadism, and ambiguous genitalia in males and females, to nonclassic hyperandrogenic symptoms in children and young women (193). In mild forms, elevated ACTH levels overcome these critical deficiencies, and the diagnosis of this disorder relies on the relationship of -5 and -4 steroids. A marked elevation of DHEA and DHEAS in the presence of normal, or mildly elevated, testosterone or androstenedione can suggest the initiation of a


Gynecology_Novak

Gynecology_Novak. relies on the relationship of -5 and -4 steroids. A marked elevation of DHEA and DHEAS in the presence of normal, or mildly elevated, testosterone or androstenedione can suggest the initiation of a screening protocol for 3β-hydroxysteroid dehydrogenase deficiency using exogenous ACTH stimulation (191). Following intravenous administration of a 0.25-mg ACTH(1-24) bolus, within 60 minutes 17hydroxypregnenolone levels rise significantly in women with 3β-hydroxysteroid dehydrogenase deficiency, compared with normal women (2,276 ng/dL compared with normal of 1,050 ng/dL). The mean poststimulation ratio between 17-hydroxypregnenolone and 17-OHP is markedly elevated (mean ratio of 11 compared with 3.4 in normal controls and 0.4 in 21-hydroxylase deficiency). The rarity of this disorder indicates that routine screening of hyperandrogenic patients is not justified (191,192).


Gynecology_Novak

Gynecology_Novak. Treatment of Adult-Onset Congenital Adrenal Hyperplasia Many patients with congenital AOAH do not need treatment. Glucocorticoid treatment should be avoided in asymptomatic patients with AOAH because the potential adverse effects of glucocorticoids probably outweigh any benefits (180,182). Glucocorticoid therapy is recommended only to reduce hyperandrogenism for those with significant symptoms. Dexamethasone and antiandrogen drugs (both cross the placenta) should be used with caution and in conjunction with oral contraceptives in adolescent girls and young women with signs of virilization or irregular menses. When fertility is desired, ovulation induction might be necessary, and a glucocorticoid that does not cross the placenta (e.g., prednisolone or prednisone) should be used (179).


Gynecology_Novak

Gynecology_Novak. Many patients who are undiagnosed but who actually have AOAH are treated with therapies for ovarian hyperandrogenism and/or PCOS, with progestins for endometrial regulation, clomiphene or gonadotropins for ovulation induction, or progestins and antiandrogens for control of hirsutism. These therapies may be appropriate, as an alternative to glucocorticoid therapy, even when AOAH is recognized as the cause for the patient’s symptoms.