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Update: The Pathogenesis and Treatment of PCOS

Kathryn M. Hill, RNC, WHCNP, MS

olycystic syndrome ture of the syndrome began to emerge. (PCOS) is the most common Understanding and appreciating the het- P endocrine disturbance in erogeneous aspect as it relates to the clin- women of reproductive age,affecting 5% ical presentation,workup,and treatment, to 10% of women in this age group. Sev- as well as an interpretation of published enty-five percent of women with sec- studies, is a key point in this article. ondary meet the diagnostic category for PCOS. ■ The Normal Stein and Leventhal first described Knowledge of hypothalamic, pituitary, an association between amenorrhea and ovarian, and endometrial events of the polycystic in 1935.1 From an in- normal menstrual cycle is essential to un- fertile population observed at laparo- derstand the aberrations associated with tomy, they described obese women with PCOS (see Figure: “The Normal Men- amenorrhea, , and enlarged, Irregular menstrual cycles, acne, and strual Cycle”).5 Briefly, pulsatile release cystic ovaries (defined as thickened cap- hirsutism often cause women to present of -releasing hormone sule,multiple,subcortical cysts in a neck- (GnRH) from the arcuate nucleus of the to a primary care setting. This article lace pattern, and increased stromal medial basal hypothalamus stimulates density). Originally only described in demonstrates how to take a careful his- pulsatile release of follicle-stimulating obese women, the condition is now hormone (FSH) and luteinizing hor- tory, perform a , known to occur in all body types. mone (LH) from the anterior pituitary. Stein and Leventhal’s initial descrip- and order the laboratory tests necessary Every menstrual cycle begins when tion of the ovaries led to the current,clas- to diagnose polycystic ovary syndrome FSH levels rise in response to decreasing sic ultrasonographic findings and an and levels at the overemphasis on morphologic ovarian (PCOS). Managing PCOS complaints and end of the previous luteal phase. Re- findings as a key component to PCOS di- maintaining important health issues are sponding to rising FSH, a cohort of fol- agnosis. Other conditions associated licles begins to grow and develop. The also addressed, as well as when to re- with polycystic ovaries (defined as ≥ 10 theca cells within the follicles respond to 2-8 mm cysts on ultrasound examina- fer to a specialist. LH and produce (androstene- tion) are Cushing’s syndrome, congeni- dione and testosterone), which are con- tal adrenal hyperplasia, and ovarian or adrenal tumors.2,3 The verted to (estrone and estradiol) in the granulosa identification of polycystic ovaries on ultrasound is clearly cells influenced by FSH. As estrogen levels rise, FSH secretion not specific for PCOS diagnosis. from the pituitary is inhibited, and most follicles undergo In 1963, Goldzieher and Axelrod4 further characterized atresia. The single, dominant follicle that emerges has in- this syndrome by determining the incidence of signs and creased FSH receptors on the granulosa cells and is therefore symptoms in a PCOS population (see Table:“Signs and Symp- able to maintain growth even as central FSH concentrations

toms of PCOS”). An understanding of the heterogeneous na- decline. The rising estrogen level triggers the onset of a mid- Illustration by Darren Hopes

8 The Nurse Practitioner • Vol. 28, No. 7 www.tnpj.com Update: The Pathogenesis and Treatment of PCOS

cycle LH surge, resulting in A complete understanding As many as 40% to 50% of young, 34 to 36 hours later.The granulosa cells, obese women with PCOS and 8% to 10% of PCOS pathogenesis is influenced by estrogen, acquire LH re- of lean women with the disorder have ei- ceptors as the cycle progresses. still elusive. The syndrome ther impaired glucose tolerance (IGT) or 6-8 Following ovulation, LH stimula- heterogeneity reinforces its multifacto- mellitus (DM), as compared tion of the granulosa cells results in with 5% of age-matched controls in the progesterone production. Rising estro- rial nature. The endocrine, reproductive, general population.9 IGT and DM are de- gen levels during the first half of the cy- and metabolic consequences of PCOS, fined as a fasting blood sugar (FBS) level cle (the proliferative phase) stimulate of 110-125 mg/dl and > 126 mg/dl, respec- in varying degrees, include increased increased endometrial thickness and tively. The 2-hour glucose tolerance test vascularity. Progesterone production circulating LH levels, with normal-to- (GTT) values for IGT and DM are 140-199 following ovulation (the secretory mg/dl and > 200 mg/dl, respectively.10 Cur- low FSH secretion leading to increased phase) stimulates increased glandular rent research focuses on the hypothesis that secretion and vessel tortuosity within ovarian and adrenal produc- resistance and accompanying hy- the . In the absence of tion and resulting in acne and hirsutism. perinsulinemia observed in obese and non- , progesterone and estrogen obese women with PCOS is the result of a levels fall after about 14 days, the en- genetic defect.11 This defect may also be re- dometrium is sloughed, and a new cycle begins. sponsible for the increased LH pulse amplitude and frequency leading to the observed with PCOS. The ■ Pathogenesis of PCOS heterogeneous clinical expression may be related to the vari- A complete understanding of PCOS pathogenesis is still elu- ation in penetrance of a single, or multiple, genetic defect. sive. The syndrome heterogeneity reinforces its multifactorial nature. The endocrine, reproductive, and metabolic conse- ■ Clinical Manifestations quences of PCOS, in varying degrees, include increased cir- Menstrual Dysfunction culating LH levels, with normal-to-low FSH secretion leading PCOS-associated menstrual dysfunction usually extends be- to increased ovarian and adrenal androgen production and yond the typical irregularity associated with the first 1-2 years resulting in acne and hirsutism. Other problems are the fail- following , and varies from subtle irregularity to ure of a dominant follicle to mature and ovulate, resulting in amenorrhea. The endometrium is in an unopposed estrogen menstrual cycle irregularities and , and insulin re- state caused by atresia and the resulting anovu- sistance, which has been associated with acanthosis nigricans. lation, leading to endometrium proliferation. Bleeding, often unpredictable and heavy, represents the sloughing of only the top layer of the endometrium that can no longer be sustained Signs and Symptoms of PCOS by estrogen production. In women of reproductive age, PCOS Signs/Symptoms Mean Incidence (%) explains 85% to 90% of and 30% to 40% of amenorrhea.12 Infertility 74 Hirsutism 69 Hirsutism and Acne Approximately 70% of women with PCOS are hirsute. It is Amenorrhea 5 important to remember that hirsutism is the accumulation Obesity 41 of terminal hairs in a male distribution pattern, not the gen- Functional bleeding 29 eral increase of vellus hair (hypertrichosis) that can vary 23 among ethnic groups. PCOS-associated hirsutism is depen- dent on overall androgen levels, sex hormone-binding glob- Corpus luteum at 22 ulin (SHBG) levels, individual skin androgen metabolism, Virilization 21 and ethnic and genetic factors and their effects on the pilose- Ovulation (indicated by biphasic baceous unit (PSU).13 body temperature chart) 15 For biologic effect, androgens must be peripherally Cyclic menses 12 metabolized. Dehydroepiandrosterone, (DHEA), dehy- droepiandrosterone sulfate (DHEA-S), and androstene- Adapted from Goldzieher JW, Axelrod LR: Clinical and biochemical features of polycystic ovarian . Fertil Steril 1963;14:631. dione are converted to testosterone. Testosterone is then metabolized to the more potent dihydrotestosterone

www.tnpj.com The Nurse Practitioner • July 2003 11 Update: The Pathogenesis and Treatment of PCOS

(DHT), which is mediated by 5α-reductase activity in the Obesity hair follicle. The anagen (growth) phase of the hair cycle Although obesity was traditionally associated with PCOS, is prolonged in hyperandrogenic states, resulting in in- about 50% of women with PCOS are not obese,14 an impor- creased terminal hair.13 These effects are more noticeable tant fact to remember when evaluating women with anovu- in women with darker hair. lation and hyperandrogenism. The obesity commonly Increased PCOS-associated androgen levels also stimu- observed in PCOS is characterized by an increased waist-to- late sebaceous gland cell division,13 which leads to increased hip ratio, referred to as android obesity,15,16 as opposed to the sebum production and the resulting acne frequently seen in truncal obesity associated with Cushing’s syndrome.The cause patients with PCOS. SHBG levels also influence the biologic of PCOS obesity has not been fully delineated. Obesity ap- effects of testosterone. When SHBG levels are decreased, as is pears to have a synergistic, deleterious effect on glucose toler- often the case in PCOS, a greater percentage of testosterone ance in women with PCOS,as noted by the increased incidence is free or unbound and, therefore, biologically active. of IGT and DM in obese women compared to lean women.

Infertility The Normal Menstrual Cycle Goldzieher and Axelrod17 found that approximately 75% of women with PCOS experience infertility.This Follicular development was a fact observed in obese women with PCOS, and the incidence of infertility in lean women with PCOS may be less. An estimated 40% of all female infertil- ity can be attributed to ovulatory dysfunction.18

Endometrium ■ Diagnosis PCOS diagnosis should be considered when women present with complaints such as menstrual cycle dys- function, hirsutism, and infertility. The development 1 7 14 21 28 of a diagnostic category has been difficult because of the heterogeneous nature of PCOS. Endocrinologists 80 disagree over the appropriate criteria required for di- agnosis, and varying inclusion criteria complicates 60 reviews of PCOS studies. A generally accepted, clinically useful definition 40 established at a National Institutes of Health consen-

mlU/mL sus conference in 1990 includes irregular menstrual 20 bleeding (> every 35 days or < 8 menses per year), LH FSH androgen excess, and the exclusion of other meta- 0 bolic disorders.19

400 Estradiol History A careful and thorough history is important in pa- 200 tients presenting with menstrual dysfunction, signs

pg/mL of androgen excess, and infertility. A family history 0 of oligomenorrhea, amenorrhea, hirsutism, and in- is suggestive of PCOS. A positive family his- 20 Progesterone tory of diabetes is associated with a higher incidence of IGT or frank diabetes in the patient with PCOS. It is important to ask the patient about the tim- pg/mL ing of symptom onset and progression as it relates to 0 menstrual irregularity and hirsutism. Patients with 1 7 14 21 28 PCOS commonly complain of menstrual irregular- Reprinted with permission from Figure 39-1. Katzung B: Basic and Clinical Pharmacology, ity beginning with menarche, and are not limited to 6th Edition. New York: McGraw Hill 1995; 609 the common 1-2 years of irregularity until the hypo-

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thalamic-pituitary-ovarian axis matures PCOS diagnosis should be system has been used extensively for ob- and regular ovulation ensues.20 For cer- jective evaluation; a score of 8 or higher considered when women tain women, the irregularity may not be- is diagnostic of hirsutism.21 Alopecia (es- gin until they are in their late teens or present with complaints pecially temporal) should be noted, as early twenties. PCOS bleeding episodes such as menstrual cycle dysfunction, well as the presence and severity of acne. often lack preceding symptoms, such as Obesity, if present, should be character- breast tenderness or bloating, suggesting hirsutism, and infertility. The develop- ized (android obesity is characteristic of anovulatory bleeding. ment of a diagnostic category has been PCOS). Hirsutism and acne, when present, The patient should be evaluated for difficult because of the heterogeneous have a gradual onset. Rapid onset and signs of Cushing’s syndrome, including signs of virilization are more suggestive nature of PCOS. Endocrinologists dis- truncal obesity, striae, moon face, hyper- of an ovarian or adrenal androgen-pro- tension, spontaneous ecchymosis, buf- agree over the appropriate criteria re- ducing neoplasm. A careful medication falo hump, and muscle weakness. Signs history is important because many drugs quired for diagnosis, and varying inclu- of virilization, such as a deepened voice have been associated with hirsutism, in- sion criteria complicates reviews of and clitoromegaly, should be assessed, as cluding antiepileptics such as phenytoin well as signs of galactorrhea. Acanthosis (Dilantin),valproate (Depakote),valproic PCOS studies. nigricans, if present, usually presents on acid (Depakene), such as the nape of the neck or in intertriginous (Betnelan,Celestone), (Cortone),dex- areas of the body, such as the axillae, under the breasts, or the amethasone (Decadron), (Florinef), hydrocor- medial aspect of the thighs. tisone (Cortef), (Medrol), and (Deltasone), and androgens and anabolic agents such as dana- Laboratory Findings and Differential Diagnosis zol (Danocrine, Cyclomen), testosterone (Andro 100, Andro- PCOS remains largely a diagnosis of exclusion (see Table:“Dif- derm, Testoderm), and minoxidil (Loniten, Rogaine). ferential Diagnoses and Biochemical Markers in Menstrual Ir- regularity and Hirsutism”). DHEA-S should be measured Physical Examination because of its longer half-life; DHEA levels are too variable to The physical examination should include a search for termi- be useful.Androgen level measurements rule out tumor. There nal hair in areas uncommon in women, such as the upper lip, is no need to measure free testosterone, androstenedione, or chin, chest, upper and lower back, upper and lower abdomen, SHBG, as these are not beneficial to the evaluation. and upper arms and thighs. The Ferriman-Gallwey scoring There is no consensus regarding insulin resistance test- ing in women suspected of PCOS. Al- though frank diabetes testing is appropriate Differential Diagnoses and Biochemical Markers in Menstrual when suspected, it is not currently known if Irregularity and Hirsutism identifying insulin resistance predicts re- sponse to insulin-sensitizing medications Differential Diagnosis Biochemical Marker for treating infertility, or if treating insulin Thyroid disease TSH resistance decreases the incidence of devel- Hyperprolactinemia Prolactin, fasting A.M. oping diabetes. A 2-hour oral GTT may provide prog- Late-onset congenital 17-OHP, fasting A.M. drawn in follicular phase, nostic value as epidemiologic evidence adrenal hyperplasia elevated levels confirmed by ACTH stimulation test supports IGT as a for develop- Ovarian tumor Total testosterone ing diabetes. The clinician must decide which laboratory values are pertinent based Adrenal tumor DHEA-S on the prevalence of the suspected disor- Premature ovarian FSH, day 3 of spontaneous or withdrawal bleed der, cost, patient and family history, and the failure (only if amenorrhea after established normal findings of the physical examination. pattern)

Pregnancy ß-hCG Imaging Studies Imaging studies are not generally helpful Note: Normal value range will vary by laboratory and assay. Check the reference ranges of the specific for establishing a PCOS diagnosis. On ul- evaluating facility. trasound, 20% of normally ovulating

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Update: The Pathogenesis and Treatment of PCOS

women will have evidence of polycystic PCOS remains largely a ceptives are not effective.Pregnancy must ovaries. However, if the DHEA-S level is be prevented with retinoid use because diagnosis of exclusion. > 700 mcg/dl and an adrenal tumor is of the teratogenic effects. suspected,a computed tomography (CT) DHEA-S should be mea- Long-acting gonadotropin-releasing scan with contrast of the adrenals is rec- sured because of its longer half-life; hormone agonist (Lupron) therapy is not ommended. If total testosterone is signif- indicated for hirsutism because it induces icantly elevated, an ultrasound may DHEA levels are too variable to be use- a hypoestrogenic state. The use of gluco- identify an ovarian tumor. ful. Androgen level measurements rule corticoids, such as , in the absence of 21-hydroxylase deficiency is out tumor. There is no need to measure ■ Management of Associated not warranted therapy for hirsutism, as Disorders and Health Consequences free testosterone, androstenedione, or PCOS hyperandrogenism is a result of Treatment goals include suppression of ovarian androgen production. The asso- SHBG, as these are not beneficial to the hyperandrogenism to improve hirsutism ciation of and increased and acne, resumption of reproductive evaluation. There is no consensus re- insulin resistance would be an additional function in those desiring fertility, protec- garding insulin resistance testing in concern in this patient population. tion of the endometrium, and reduction , an an- of long-term risks of type 2 diabetes and women suspected of PCOS. Although tagonist and competi- cardiovascular disease. No monotherapy frank diabetes testing is appropriate tor, can be beneficial in hirsutism treats all aspects of PCOS and, in fact, treatment,22 but does not have FDA ap- when suspected, it is not currently known many treatments are mutually exclusive. proval for this indication.Spironolactone if identifying insulin resistance predicts is best used with a combination oral con- Hirsutism and acne traceptive because of its association with response to insulin-sensitizing medica- Hirsutism and acne, two clinical signs of menstrual irregularity in up to 50% of hyperandrogenism, can be distressing to tions for treating infertility, or if treating patients (as a result of mild progestational 23 patients.The goals of therapy are to lower insulin resistance decreases the inci- activity) and possible teratogenic effect. androgen levels, increase SHBG to allow Dosing should begin at low levels and less bioactive circulating testosterone, dence of developing diabetes. gradually increased (25 mg q.d. for 2 and if necessary, hair removal. There are weeks,followed by 50 mg q.d.for 2 weeks, two hirsutism therapy categoriescosmetic hair removal and then increased to 50-100 mg b.i.d.) to avoid mild diuretic ef- pharmacotherapy, which can either reduce androgen produc- fects. Spironolactone should be discontinued 3 months prior tion or decrease the effects on the skin. Cosmetic therapies to conception attempts. include plucking or tweezing, waxing, shaving, depilatories, Flutamide,a 5α-reductase inhibitor indicated for prostate electrolysis, and laser treatments. These therapies do not af- cancer, has been proposed as an alternative to spironolactone fect the rate of hair growth and are only temporary measures, for hirsutism treatment, however, conflicting data exist re- however electrolysis and laser treatments may provide more garding its effectiveness compared with spironolactone.24,25 permanent results. A 6-12 month pretreatment with medical Flutamide may have a slower return of symptom rate once therapy to allow for new hair growth suppression may help discontinued. Finasteride, a type II 5α-reductase specific in- avoid re-treatment. hibitor indicated for androgenic alopecia, has potential Medical therapies limit new hair growth, but do not af- toxicity and shows no clear advantage over spironolactone.26 fect existing hair. Therefore, it may take 6-12 months of ther- Vaniqa is a topical cream for facial hair removal, but there is apy before an effect is appreciated, and 18 months or longer no published data on clinical trials. to see a full effect. Pharmacotherapy is also a temporary mea- sure and the benefits are lost when the treatment is discon- Obesity tinued. Obesity is a well-recognized risk factor for developing type 2 The FDA has not approved oral contraceptive treatment diabetes, and 50% of PCOS patients are obese. The cause of of hirsutism,and only OrthoTri-Cyclen and Estrostep received obesity or how it is involved in developing diabetes is not clear. an FDA-approved indication for acne. No one oral contra- Research shows that the endocrine and ovarian function ceptive has proven to be a better treatment for hirsutism and of obese women with PCOS can be improved (decreased in- acne, although individual responsiveness exists. Topical ben- sulin levels, increased SHBG, and spontaneous resumption zoyl peroxide, retinoids (topical or systemic), and antibiotics of menses) with as little as a 5% weight loss.27 As with any (topical or systemic) are sometimes used when oral contra- weight loss therapy, the challenge is to maintain the loss.

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Weight reduction can be encouraged The FDA has not approved and low HDL-C levels associated with as a first-line solo therapy and should be non-PCOS insulin resistant states, so it oral contraceptive treat- included with medical treatment for an- remains unclear what additional risk of drogen reduction, menstrual regulation, ment of hirsutism, and only CVD disease exists in PCOS women in- and for those desir- OrthoTri-Cyclen received an FDA-ap- dependent of obesity. ing fertility. Weight reduction is expected In a retrospective cohort, long-term to reduce the risk of and proved indication for acne. No one oral follow-up study of PCOS women in the dyslipidemia associated with obesity. The contraceptive has proven to be a better UK,32 an increased prevalence of cardio- insulin resistance of PCOS does not con- vascular risk factors was demonstrated, treatment for hirsutism and acne, although fer additional risk, other than the obesity but no excess of cardiovascular disease alone, for developing hypertension and individual responsiveness exists. Topi- was found in middle-aged women. dyslipidemia,28 although long-term, Large-scale prospective trials of PCOS cal benzoyl peroxide, retinoids (topical prospective,controlled studies are needed women are needed to help us elucidate to confirm this. or systemic), and antibiotics (topical or the etiology of heart disease in this pop- systemic) are sometimes used when oral ulation and if PCOS actually confers pro- ■ Hyperinsulinemia and Dyslipidemia tection from CVD through yet unclear IGT is a known risk factor for type 2 di- contraceptives are not effective. Preg- mechanisms. abetes and is associated with PCOS. Data nancy must be prevented with retinoid Currently,there is no standard regard- from the Diabetes Prevention Program,29 ing routine screening for dyslipidemia in use because of the teratogenic effects. a large study of both men and women women with PCOS. Screening for lipid with IGT, demonstrated a 29% conver- abnormalities may be warranted, how- sion to type 2 diabetes over 3 years when only standard lifestyle ever, if IGT or diabetes is discovered. interventions were employed. A 58% reduction in develop- ing type 2 diabetes was seen with intensive lifestyle interven- ■ Menstrual Dysfunction tions alone (aimed at a 7% weight reduction and 150 minutes The endometrium can be protected from unopposed estro- of physical activity per week). Only a 31% reduction was seen gen and regular, scheduled, withdrawal bleeding can be ac- when the insulin-sensitizing drug metformin (Glucophage) complished with combination oral contraceptives or cyclic was combined with standard lifestyle interventions. progesterone. The standard contraindications and precautions No large-scale prospective studies have followed well- for oral contraceptive use apply to this population. Medrox- defined PCOS women into to characterize their yprogesterone in dosages of 5-10 mg p.o. every day for progression of glucose tolerance. These studies are needed 5-10 days, Prometrium 400 mg p.o. every day for 10 days, and before we can determine the best use of these drugs in this Crinone vaginal cream 4-8% every other day for 6 doses all population. have FDA indication for secondary amenorrhea. Wild et al reported that women with hirsutism have a statistically significant decrease in HDL cholesterol and a sta- ■ Infertility tistically significant increase in triglycerides and choles- To reduce pregnancy complications, weight reduction should terol/HDL ratios.30 be the first-line treatment for all obese patients seeking fertil- Subsequently, Legro et al 31 studied a well-characterized ity. When this is not successful, pharmacotherapy should be group of non-Hispanic, nondiabetic, white PCOS women implemented. ages 18 to 45 years old. After adjusting for age, use, Clomiphene citrate (CC) has been the mainstay of ovu- , and activity level, higher total cholesterol and LDL- lation induction for women with PCOS in the C levels were found in both obese and non-obese PCOS since 1967. Because the focus of treating PCOS patients with women compared to their controls. CC is correction of the anovulatory state while keeping mul- Obese PCOS women had higher HDL-C levels compared tiple birth risk low, treatment should be started with the low- to obese controls. Triglycerides were similar among groups. est available dose (50 mg), with 50 mg increments of increased Although obese women had cholesterol/HDL-C ratios in the dosage if ovulation is not detected. There is no advantage to highest quartile, the ratios were lower in obese PCOS women, increasing the dose if ovulation occurs on a lower dose. Of possibly reducing their risk of cardiovascular disease (CVD) oligomenorrheic women, 93% to 95% ovulate with CC.33,34 compared to other obese women. Previous studies in PCOS Approximately 50% of women will conceive at the 50 mg women did not adjust for weight and ethnicity. The findings 5-day dosage. An additional 20% of women conceive at the 100 of this study were not consistent with the elevated triglyceride mg dose. The majority of (84.5%) occur during the

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Update: The Pathogenesis and Treatment of PCOS

Patient Education: Polycystic Ovary Syndrome

What is Polycystic Ovary Syndrome? Are there risks to my health if Polycystic ovary syndrome (PCOS) re- I have PCOS? sults from an imbalance in the hormones Certain women with PCOS are at greater that regulate the normal menstrual cy- risk for developing diabetes and cardio- cle. The ovary fails to develop and release vascular disease. This risk is increased if a single egg each month. This leads to you are . As many as 40% to the often-seen “cystic” appearance of the 50% of young, obese women with PCOS ovaries (multiple small fluid-filled sacs and 8% to 10% of lean women with the within the ovary). disorder have either impaired glucose tol- erance (IGT) or diabetes mellitus (DM), What causes PCOS? as compared with 5% of age-matched The cause is not known. Researchers are controls in the general population. investigating the possibility of a genetic cause. What are the treatments for PCOS? You and your health care provider will How common is PCOS? decide your treatment. Treatment often PCOS is the most common endocrine disturbance in women includes oral contraceptives (birth control pills) to regulate of reproductive age, affecting 5% to 10% of women in this your menstrual periods. These medications may also reduce age group. Seventy-five percent of women with secondary excessive hair growth and acne. Some women may use other amenorrhea meet the diagnostic category for PCOS. medications (progesterone) monthly to regulate their men- strual periods. Women who want to become pregnant may What are the symptoms of PCOS? need to use a special medication called clomiphene citrate Common symptoms include menstrual cycle irregularity, that will help release an egg every month. ranging from unpredictable periods (often, periods with a heavy blood flow) to not having a menstrual period. Other What if I have an impaired glucose tolerance? common symptoms include excessive body hair (hirsutism) If you have an impaired glucose tolerance test, you are at risk for developing diabetes. You will need to start chang- and acne. ing your eating habits. Limit concentrated sweets and sim- ple carbohydrates to reduce your weight if you are Do I have to be overweight to have PCOS? overweight. You may need to start medication to control No.Although obesity was traditionally associated with PCOS, your blood sugar if you develop diabetes. about 50% of women with PCOS are not obese. The obesity commonly observed in PCOS is characterized by an increased For further information: waist-to-hip ratio, referred to as android obesity, as opposed PolyCystic Ovarian Syndrome Association to the truncal obesity associated with Cushing’s syndrome. Web site: http://www.pcosupport.org The cause of PCOS obesity has not been fully delineated. Obe- American Society for Reproductive Medicine sity appears to have a synergistic, deleterious effect on glu- 1209 Montgomery Highway cose tolerance in women with PCOS,as noted by the increased Birmingham, AL 35216-2809 incidence of IGT and DM in obese women compared to lean 205-978-5000 women. Web site: http://www.asrm.org Illustration by Darren Hopes

www.tnpj.com The Nurse Practitioner • July 2003 21 Update: The Pathogenesis and Treatment of PCOS

first 3 ovulatory cycles. Increased body To reduce pregnancy com- tiveness of metformin on lean PCOS weight is associated with a need for in- women unclear. Additionally, there are plications, weight reduc- creased dosage to achieve ovulation. If the no published large-scale clinical trials patient has remained anovulatory after tion should be the first-line demonstrating metformin’s impact on doses of 150 mg or has not conceived after treatment for all obese patients seeking live birth rates in PCOS women, nor do 3 ovulatory cycles, refer her to a reproduc- any head-to-head randomized trials ex- tive endocrinology practice for further as- fertility. When this is not successful, phar- ist comparing metformin to CC as ini- sessment and treatment,which may include macotherapy should be implemented. tial therapy for ovulation induction. insulin-sensitizing agents (to treat insulin Clomiphene citrate (CC) has been the resistance), gonadotropin injections, or la- ■ Summary paroscopic ovarian drilling (to reduce an- mainstay of ovulation induction for PCOS is common among women of re- drogen levels). productive age, with endocrine, repro- women with PCOS in the United States An increasing number of reports re- ductive, and metabolic consequences. view the use of insulin-sensitizing drugs since 1967. Because the focus of treat- Although not fully understood, research for the treatment of PCOS. Metformin ing PCOS patients with CC is correction indicates that the cause is the unique (Glucophage) has been best studied in and intrinsic insulin resistance associ- this regard, including its effectiveness in of the anovulatory state while keeping ated with the syndrome. Treatment restoring regular menstrual cycles, initi- multiple birth risk low, treatment should should focus on reduction of androgen- ating ovulation induction, reducing rates associated symptoms, protection of the be started with the lowest available dose of spontaneous miscarriage and gesta- endometrium, weight loss if obese, re- tional diabetes, and correcting metabolic (50 mg), with 50 mg increments of in- ducing long-term risk of diabetes and abnormalities associated with PCOS.35,36 cardiovascular disease, and resumption creased dosage if ovulation is not de- Guidelines are being established for its of fertility, if desired. use in the treatment of infertility in PCOS tected. After a careful history, physical ex- women.37 It is already FDA approved for amination, and laboratory testing to rule the treatment of type 2 diabetes. out metabolic causes for the symptoms,NPs can manage most Treatment with metformin is aimed at lowering the hy- of the common complaints and health maintenance issues perinsulinemia associated with PCOS, thereby reducing an- associated with PCOS. If non-PCOS causes of oligomenor- drogen production and facilitating ovulation. The reduced rhea or hirsutism, such as Cushing’s syndrome, adult onset insulin levels would theoretically lower the risk of developing congenital adrenal hyperplasia or adrenal or ovarian tumors DM or cardiovascular disease. are found during the workup, the patient should be referred Although studies evaluated in the review articles demon- to an endocrinologist for treatment. If fertility is desired, a strated a 60% return to normal menstrual cycles and ovula- reproductive endocrinologist should be consulted. tion after 3 to 6 months of treatment using metformin alone REFERENCES in an unselected population of PCOS women (PCOS women 1. Stein IF,Leventhal ML:Amenorrhea associated with bilateral polycystic ovaries. not shown to be CC-resistant), there were no good data avail- Am J Obstet Gynecol 1935;29:181-91. able on pregnancy rates. In this population of women, the ad- 2. Polson DW, Adams J, Wadsworth J, et al.: Polycystic ovaries-A common find- ing in normal women. Lancet 1988;1:870-72. dition of CC to metformin for a total duration of 8 to 9 months 3. Franks S: Polycystic ovary syndrome. N Engl J Med 1995;333:853-61.[Erra- resulted in an approximate 66% ovulation and 34% preg- tum: N Engl J Med 1995;333:1435.] 4. Goldzieher JW, Axelrod LR: Clinical and biochemical features of polycystic nancy rate. This compares to an ovulation and pregnancy rate . Fertil Steril 1963;14:631. using CC alone as first-line therapy for ovulation induction 5. Katzung B. Basic and Clinical Pharmacology. 6th edition. New York, N.Y.: Mc- Graw-Hill, 1995;609. in PCOS women of 70-80% and 33-45% respectively. Not all 6. Dunaif A, Finegood DT: Cell dysfunction independent of obesity and glucose studies showed universal beneficial effects on androgen lev- intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:942-47. els, insulin levels or body mass index. 7. Legro R, Finegood D, Dunaif A: A fasting glucose to insulin ratio is a useful In CC-resistant PCOS women, the ovulation and preg- measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:2694-98. nancy rates were 40% and 25% respectively in both metformin 8. Legro RS, Kunselman AR, Didson WC, et al.: Prevalence and predictors for alone and metformin plus CC groups. type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A prospective, controlled study in 254 affected women. J Clin En- These studies must be viewed with caution and as pre- docrinol Metab 1999;84:165-69. liminary results since there are a limited number of studies, 9. Harris MI, Hadden WC, Knowler WC, et al.: Prevalence of diabetes and im- paired glucose tolerance levels in US population aged 20-74 years. Diabetes many were small in numbers and observational, and most 1987;36:523-34. were performed on obese PCOS women, leaving the effec- 10. Report of the expert committee on the diagnosis and classification of diabetes

22 The Nurse Practitioner • Vol. 28, No. 7 www.tnpj.com Update: The Pathogenesis and Treatment of PCOS

mellitus. Diabetes Care 1997;20:1183-97. 27. Kiddy DS, Hamilton-Fairley D, Bush A, et al: Improvement in endocrine and 11. Dunaif A: Insulin resistance and the polycystic ovary syndrome: Mechanisms ovarian function during dietary treatment of obese women with polycystic and implications for pathogenesis. Endocr Rev 1997;18:774-800. ovary syndrome. Clin Endocrinol 1992;36:105-11. 12. Franks S, White DM: Prevalence of and etiological factors in polycystic ovar- 28. Graf MJ, Richards CJ, Brown V, et al: The independent effects of hyperandro- ian syndrome. Ann N Y Acad Sci 1993;687:112. genism, hyperinsulinemia, and obesity on lipid and lipoprotein profiles in 13. Lobo RA: Androgen excess. In: Daniel RM Jr, Val D, Rogerio L, eds. Infertility, women. Clin Endocrinol 1990;33:119-31. Contraception and Reproductive Endocrinology. 3rd edition. New York, N.Y.: 29. Diabetes Prevention Program Research Group: Reduction in the incidence of Blackwell Scientific, 1991;422-46. type 2 diabetes with lifestyle intervention or metformin.N Engl J Med 2002;346: 14. Pasquali R, Antenucci D, Casimirri F, et al: Clinical and hormonal characteris- 393-403. tics of obese amenorrheic hyperandrogenic women before and after weight 30. Wild RA, Alapovic P, Parker J: Lipid and apolipoprotein abnormalities in hir- loss. J Clin Endocrinol Metab 1989;68:173-79. sute women. The association with insulin-resistance. Am J Obstet Gynecol 15. Evans DJ, Barth JH, Burke CW: Body fat topography in women with andro- 1992;166:1191-97. gen excess. Int J Obes 1988;12:157-63. 31. Legro RS, Kunselman AR, Dunaif, A: Prevalence and predictors of dyslipidemia 16. Franks S: Polycystic ovary syndrome. N Engl J Med 1995;333:853-61. in women with polycystic ovary syndrome. Am J Med 2001;111:607-613. 17. Goldzieher JW, Axelrod LR: Clinical and biochemical features of polycystic 32. Wild S, Pierpoint T, McKeigue P, et al: Cardiovascular disease in women with ovarian disease. Fertil Steril 1963;14:631. polycystic ovary syndrome at long-term follow-up: a retrospective cohort 18. . In: Speroff L, Glass RH, and Kase NG, eds. Clinical Gyneco- study. Clin Endocrinol 2000;52:595-600. logic Endocrinology and Infertility. 5th edition. Baltimore, Md.: Williams and 33. Gysler M, March CM, Mishell DR, et al: A decade’s experience with an indi- Wilkins, 1994;809-39. vidualized clomiphene treatment regimen including its effect on the post- 19. Dunaif A, Segal KR, Shelley DR, et al: Evidence for distinctive and intrinsic de- coital test. Fertil Steril 1982;37:161-67. fects in insulin action in polycystic ovary syndrome. Diabetes 1992;41:1257-66. 34. Lobo RA, Gysler M, March CM, et al: Clinical and laboratory predictors of 20. Yen SSC: The polycystic ovary syndrome. Clin Endocrinol 1980;12:177-208. clomiphene response. Fertil Steril 1982;37:168-74. 21. Ferriman D, Gallwey JD: Clinical assessment of body hair growth in women. 35. Costello MF, Eden JA: A systematic review of the effects J Clin Endocrinol Metab 1961;21:1440-47. of metformin in patients with polycystic ovary syndrome. Fertil Steril 2003;79:1-13. 22. Barth JH, Cherry CA, Wojinarowska F, Dawber RP: Spironolactone is an ef- fective and well tolerated systemic antiandrogen therapy for hirsute women. 36. Haas, DA, Carr BR, Attia, GR: Effects of metformin on body mass index, men- J Clin Endocrinol Metab 1989;68:966-70. strual cyclicity, and ovulation induction in women with polycystic ovary syn- drome. Fertil Steril 2003;79:469-481. 23. Chapman MG, Dorwsett M, Dewhurst CJ, Jeffcoate SL: Spironolactone in combination with an oral contraceptive: An alternative treatment for hir- 37. Nester JE, Stoval D, Akhter N, et al: Strategies for the use of insulin-sensitiz- sutism. Br J Obsetet Gynaecol 1985;92:983-85. ing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril 2002;77:209-215. 24. Cusan L, Dupont A, Gomez JL, et al: Comparison of flutamide and spirono- lactone in the treatment of hirsutism: A randomized controlled trial. Fertil ACKNOWLEDGEMENTS Steril 1994;61:281-87. The author would like to thank Laura H Greenberg, MD, and Michael McClung, 25. Erenus M, Gurbuz O, Durmusoglu F, et al: Comparison of the efficacy of MD, for their assistance in reviewing the manuscript. spironolactone versus flutamide in the treatment of hirsutism. Fertil Steril 1994;61:613-16. 26. Wong IL, Morris RS, Ghang L, et al: A prospective randomized trial compar- ABOUT THE AUTHOR ing finasteride to spironolactone in the treatment of hirsute women. J Clin Kathryn M. Hill is a Women’s Health Care Nurse Practitioner with the reproduc- Endocrinol Metab 1995;80:233-38. tive endocrinology practice of Laura H. Greenberg, MD, in Portland, Ore.

CE Test Update: The Pathogenesis and Treatment of PCOS

Instructions: Provider Accreditation: • Read the article beginning on page 8. This Continuing Nursing Education (CNE) activity for 2.5 contact hours •Take the test, recording your answers in the test answers and 1.5 pharmacology contact hours is provided by Lippincott Williams section (Section B) of the CE enrollment form. Each question & Wilkins, which is accredited as a provider of continuing education in has only one correct answer. nursing by the American Nurses Credentialing Center’s Commission on • Complete registration information (Section A) and course Accreditation and by the American Association of Critical-Care Nurses evaluation (Section C). (AACN 9722, CERP Category A). This activity is also provider approved • Mail completed test with registration fee to: Lippincott by the California Board of Registered Nursing, Provider Number CEP Williams & Wilkins, CE Dept., 16th Floor, 345 Hudson St., 11749 for 2.5 contact hours and 1.5 pharmacology contact hours. LWW New York, NY 10014. is also an approved provider of CNE in Alabama, Florida, and Iowa and • Within 3 to 4 weeks after your CE enrollment form is holds the following provider numbers: AL #ABNP0114, FL #FBN2454, IA received, you will be notified of your test results. #75. All of its home study activities are classified for Texas nursing con- • If you pass, you will receive a certificate of earned contact tinuing education requirements as Type I. hours and an answer key. If you fail, you have the option of taking the test again at no additional cost. Your certificate is valid in all states. This means that your certificate of • A passing score for this test is 12 correct answers. earned contact hours is valid no matter where you live. • Need CE STAT? Visit http://www.nursingcenter.com for immediate results, other CE activities, and your personal- Payment and Discounts: ized CE planner tool. • The registration fee for this test is $17.95. • No Internet access? Call 1-800-933-6525, ext. 331 or ext. • If you take two or more tests in any nursing journal published by 332, for other rush service options. LWW and send in your CE enrollment forms together, you may deduct • Questions? Contact Lippincott Williams & Wilkins: 212-886- $0.75 from the price of each test. 1331 or 212-886-1332. • We offer special discounts for as few as six tests and institutional bulk discounts for multiple tests. Call 1-800-933-6525, ext. 332, for Registration Deadline: July 31, 2005 more information.

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