Polycystic ovary syndrome (PCOS) is a heterogeneous metabolic disorder affecting 4%-10% of females.¹ Females with PCOS usually present with multiple problems, including infertility, oligomenorrhea, and signs of hyperandrogenism. PCOS is also associated with major metabolic and cardiovascular disease risk factors. Nurse practitioners need to use varied approaches with female patients of different ages because of the different clinical, hormonal, and metabolic features related to PCOS that manifest at different times of life. Treating PCOS early reduces complications such as diabetes mellitus and heart disease later on.^2,3 This article describes the presentation of PCOS across the lifespan and offers suggestions for management at different times in the life cycle.

Diagnostic Criteria

The definition of PCOS is fluid and controversial, making diagnosis difficult and hampering study.⁴ In 1935, Stein and Leventhal described PCOS as a syndrome characterized by obesity, hirsutism, and infertility.⁵ The team performed surgical ovarian wedge resections, the first established treatment for women with anovulatory PCOS. They discovered that women with PCOS had enlarged ovaries, thickened sclerotic capsules, and an abnormally high number of follicles. The follicles were found to exist in varying states of maturation or atresia. For today’s females with PCOS, common findings on pelvic ultrasonography include enlarged ovaries showing bright echogenic stroma and multiple small follicles at the periphery that are known as the “string of pearls.”⁶ However, a positive ultrasonographic finding is not sufficient to make a diagnosis of PCOS.

Irregular menses, hyperandrogenism, acne, and obesity are considered the hallmark findings in females with PCOS.⁷ In fact, obesity is a major problem for 40%-60% of women with PCOS.⁷ This multisystem disease is also often characterized by insulin resistance (IR), hyperinsulinemia, childhood obesity, visceral (abdominal) fat, and impaired glucose tolerance (IGT), all of which have an effect from fetal life through menopause.² In view of the congenital origins of the syndrome, it is not surprising that there is increasing recognition of PCOS in childhood.⁸ 

Clinical features of PCOS vary greatly from female to female, making diagnosis and treatment difficult. Table 1 (see sidebar) lists physical signs of PCOS,^10-17 and Table 2 (see sidebar) lists metabolic changes.^18-23 Three groups of experts have tried to delineate the diagnostic criteria specific to PCOS (Table 3 - see sidebar).^24-27 In 1990, an NIH/NICHD (National Institutes of Health/National Institute of Child Health and Human Development) conference led to the inclusion of only two criteria for a diagnosis of PCOS: chronic anovulation and clinical signs of androgen excess.²⁴ In 2003, the Rotterdam ESHRE/ASRM (European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine)-sponsored consensus workshop added oligo-ovulation as a criterion for PCOS.²⁵ In 2006, a position paper by the Androgen Excess Society defined PCOS as a predominantly hyperandrogenic syndrome.²⁷ 

In all cases, PCOS is a disease of exclusion. Table 4 lists the differential diagnosis for females who present with signs and symptoms of PCOS. The list includes entities such as non-classic congenital adrenal hyperplasia (CAH), Cushing syndrome, hyperprolactinemia, and hypogonadotropic hypogonadism, which must be ruled out or identified as being co-morbid with PCOS.²⁸ For example, CAH is found in 1%-19% of women with PCOS.²⁸ Cushing syndrome refers to chronic glucocorticoid excess—no matter what the cause. Androgen-secreting tumors, either ovarian or adrenal, are considered first if high testosterone (T) levels are present. Hyperprolactinemia and hypothyroidism are also considered, and are identified by measuring serum prolactin and serum thyroid-stimulating hormone levels, respectively.²⁸

Etiology

Genetic Factors—Insulin resistance, one of the hallmarks of PCOS, is derived in one of two ways. A severe form of IR is related to central obesity (the mechanism causing the IR is unknown).²⁹ But women of normal weight and anovulatory status can also have IR, which is related to an inherited defect in autophosphorylation of the insulin receptor. In these women, the degree of IR is relatively milder. Some women with PCOS do not have IR because they do not have the inherited defect and their weight is below the threshold to trigger it. Conversely, some obese women with IR can ovulate and not have PCOS. The most severe IR occurs in obese women with central abdominal fat and the inherited defect.²⁹

Diseases such as PCOS have a complex, multifactorial etiology in which a variety of predisposing genes, not just a single gene, interact with environmental factors to produce disease.¹⁸ Chromosome 19 may be implicated in diabetes mellitus (DM) and possibly in PCOS as well.³⁰ Evidence does support a genetic link; up to 40% of women with PCOS have an affected sister.³¹ Similarly, brothers of women with PCOS have been shown to be affected—these males tend to have elevated mean T levels.^32,33 Having a sister with PCOS may be an emerging risk factor for cardiovascular disease (CVD) in men.³⁴ Brothers of women with PCOS have been found to have a metabolic phenotype with dyslipidemia and IR.³⁵ Abnormalities in insulin action and secretion, glucose tolerance, and lipid levels also show familial aggregation in first-degree relatives of women with PCOS.³⁶

Environmental Factors—Low-birth-weight (LBW) infants, relative to their normal-weight counterparts, have a greater incidence of precocious puberty, hyperinsulinemia, and hyperandrogenism.³⁷ A correlation has also been shown between LBW and dyslipidemia and IR.^38,39 Restricted growth in a fetus or infant is thought to lead to PCOS in genetically susceptible individuals exposed to dietary excess later in life.⁴⁰ Why would a gene predispose up to 10% of women to anovulation, DM, and heart disease? Women with PCOS today, in a time of plenty, are likely to be obese, sedentary and anovulatory. When such a person loses weight, ovulation recommences. But perhaps in the past, during times of famine (or in parts of the world today where food is scarce), PCOS might confer a survival advantage to women with the “thrifty gene,” as coined by Neel,⁴¹ which provides them with famine-resistant glucose metabolism. In these women, metabolic and endocrine control systems are tuned to expect a meager food supply and are ill adapted for nutritional excess.^39,42

Low-birth-weight infants can experience catch-up weight gain later on.⁴³ Children born after fetal nutritional deprivation, of an obese mother, and later exposed to a high-calorie, high-fat diet can develop into overweight/obese teenagers or adults.⁴⁰ Subsequent programming of central metabolic processes increases the risk for developing IR and dyslipidemia.⁴² Adults with an LBW history tend to have increased fasting glucose and insulin levels; a glucose challenge causes exaggerated increases in insulin and glucose.⁴⁴ Evidence suggests that PCOS is passed from mother to daughter, but the mechanism is still not well understood.⁴⁵

PCOS Through the Life Cycle

Childhood—PCOS is usually not identified in young girls; however, those who are overweight/obese should be evaluated for the syndrome.^46,47 Early suspicion and identification of PCOS can lead to institution of preventive measures that may avert serious sequelae.⁴⁸ In taking a history, NPs seek to identify PCOS in the family and gestational influences such as high birth weight in an infant born to an overweight mother, LBW related to intrauterine growth retardation, or small size relative to gestational age. Overweight/obese girls may have early adrenarche and pubarche. The normal age range for puberty onset in girls is 8-13 years, but the age of menarche varies. Childhood obesity and premature pubarche are positively correlated with PCOS.⁴⁹

Premature pubarche is defined as having pubic hair before age 8, or before age 6 in African-American girls.⁵⁰ Premature pubarche results from adrenal androgen production. Tanner stage 2, or breast development, marks the onset of pubertal development. Premature menarche may be related to gonadotropin-dependent precocious puberty, a problem mediated by the hypothalamic-pituitary-ovarian (HPO) axis and treated with a gonadotropin-releasing hormone analog.⁵¹ A high thyroid-stimulating hormone (TSH) level may also underlie precocious puberty, so a TSH level should be obtained. 

Early Adolescence—No single set of diagnostic criteria for PCOS in early adolescence has been universally accepted. Like their adult counterparts, adolescents with PCOS are at risk for developing metabolic syndrome (Met-S), which shares many features with PCOS (Table 5).³ PCOS affects approximately 2.1% of adolescent girls and 28.7% of overweight adolescent girls.⁵²

In terms of the history, common findings suggesting an increased risk for PCOS in early adolescents include a family history of PCOS, gestational diabetes in the mother, and a family history of CVD, acne, hirsutism, dyslipidemia, infertility, and balding (in men) before they reach age 35.¹ There may also be a relationship between females with PCOS and fathers who have Met-S.⁵³   

A waist circumference exceeding 35 inches (88 cm) predicts insulin sensitivity in postmenarchal girls.⁵⁴ Many lean postmenarchal girls with PCOS have menstrual irregularities and elevated serum levels of free T, luteinizing hormone (LH), and follicle-stimulating hormone (FSH).⁵⁵ Girls with PCOS who are generally lean may still have abdominal obesity, putting them at risk for the same metabolic disturbances as their heavier counterparts. Most adolescents with PCOS show significant IR, and those who are obese bear an even heavier burden.³ 

Oligomenorrhea in the first few postmenarchal years may be an early sign of PCOS due to anovulation. However, some girls without PCOS experience physiologic anovulation during and after puberty, which lasts up to 2 years, followed by more regular ovulatory cycles. Controversy exists regarding whether this phenomenon is due to transient hyperactivity of the HPO axis, resulting in increased androgen levels.⁵⁶ As a consequence, NPs may have difficulty distinguishing between girls who will start to ovulate regularly and those who have PCOS. However, young teens may have clinical signs of PCOS, including signs of androgen excess (eg, obesity, moderate to severe acne, hirsutism), which should be recognized as PCOS. 

Hyperandrogenemia is rarely detected before age 14 or 15; T levels measured before this age may fall within normal limits. Affected girls, however, may experience rapid weight gain and signs of hyperandrogenism. For teenagers older than 15 with such symptoms, other diseases must be ruled out. These laboratory values should be obtained: FSH, LH (HPO axis), prolactin (pituitary microadenoma), and TSH (hypothyroidism). Controversy exists regarding the value of T assays. Therefore, evaluation of clinical signs of hyperandrogenism is often recommended as opposed to serum assays.²⁴

Assessment. Two years after menarche, the HPO axis acquires normal functioning, with resulting regular menses.¹⁷ Irregular cycles beyond 2 years suggest a pathologic cause such as anovulation, especially if associated with acne, hirsutism, and weight gain. In girls in whom a high suspicion for PCOS or Met-S exists, a diagnostic workup is indicated. 

Management. The importance of lifestyle changes is emphasized and framed in a positive way. For many teenage girls, overcoming internal and external obstacles to healthful dietary regimens and exercise is a challenge. NPs must determine the level of patient motivation and identify appropriate dietary and exercise programs. Use of health system resources, interdisciplinary experts such as dieticians or social workers, and community resources can aid in achieving health goals. Parents and siblings need to be involved in major family lifestyle changes. These household members should be encouraged to remove junk food from the home and replace it with more nutritious snacks. Family members should also participate in heart-healthy exercise.  

Late Adolescence—Older adolescents (ie, those 17-20 years) with PCOS present with oligomenorrhea and signs of hyperandrogenism; their T levels are also increased. One-half of these individuals are overweight or obese.⁵⁷ Excess weight aggravates anovulation, menstrual irregularities, and hyperandrogenism. These individuals may also have acanthosis nigricans, an eruption of velvety benign growths and hyperpigmentation on the skin of the axillae, neck, anogenital area, and groin, as well as on the elbows and knees, where the lesions appear white and calloused. Acanthosis nigricans, often accompanied by skin tags, is associated with IR. It diminishes with weight loss. 

Assessment. Older teenagers undergo a complete history and a physical examination, including a speculum and bimanual examination if they are sexually active. Height, weight, waist circumference, and blood pressure (BP) are measured. Laboratory tests include measurements of high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), prolactin, dehydroepiandrosterone sulfate, and 24-hour urinary-free cortisol, as well as a 2-hour oral glucose tolerance test (OGTT). T assays are considered unreliable by some experts.²⁴ Transvaginal ultrasonography may be performed, but a finding of polycystic ovaries is not diagnostic for PCOS.

Management. A main therapeutic goal for older adolescents with PCOS is restoring menses by attaining and maintaining normal body weight. This change will reduce hyperandrogenic signs. Weight reduction is difficult. Seeing patients on a monthly basis to provide support for weight loss and nutrition may be effective.

Use of combined oral contraceptives (COCs) is recommended in older adolescents with hirsutism and menstrual irregularities. These agents offer more benefit than risk for healthy nonsmokers. Not only do COCs provide a predictable withdrawal bleed, but they also protect the endometrium from the unopposed estrogen effect that accompanies oligomenorrhea. Safety of COCs depends largely on the dose of estrogen. Because all COCs are made with ethinyl estradiol, the dose of the chosen product is important; the higher the dose, the greater the risk for thromboembolic events. COCs also contain one of a variety of progestins. The progestin provides the contraceptive effect for the most part, and the estrogen helps with cycle control. Newer COC formulations with progestins related to spironolactone have benefits in reducing androgenic effects such as acne. Desogestrel is a safe progestin, but it is also relatively androgenic. COCs containing levonorgestrel or norgestrel are contained in the most widely prescribed contraceptives worldwide. All COCs can help with acne and provide endometrial protection.

Adulthood—Women with PCOS may present for care because of signs of infertility, pregnancy loss, hyperandrogenism, obesity, or other problems. For most adult women with PCOS (74%), infertility is the main complaint, followed by hirsutism and menstrual disorders.⁵⁸ Many infertile women who wish to conceive a child require ovulation induction, although success is not assured. Many women fail to respond to clomiphene citrate and pituitary gonadotropins, and some over-respond to these medications with ovarian hyperstimulation. Compared with other women receiving such treatment, they are at greater risk for multiple pregnancy.¹⁰ In overweight/obese women with PCOS, weight loss is paramount in terms of increasing the chance of ovulation. Women with PCOS are also at increased risk for developing DM and CVD.

Assessment. PCOS is identified in women in much the same way as it is in teens. Table 6 lists elements to be included in the workup, as well as the values that would suggest a diagnosis of PCOS.⁵⁹ Women of any age or weight who have PCOS are at increased risk for many health problems, including glucose intolerance, hypertension (HTN), hyperlipidemia, and CVD. As a consequence, all women with PCOS, regardless of body mass index (BMI), should undergo a 2-hour, 75-mg OGTT,⁶⁰ lipid profile, and TG measurement, as well as any other screening tests relevant to the problems they are experiencing. 

Management. Exercise and weight loss can lower BP, reduce central adiposity, and improve the lipid profile and insulin sensitivity.⁶¹ These therapeutic lifestyle changes (TLC) are always the first line of treatment. Monitoring patients’ food diaries and weight can be very helpful. Women who lose 5%-10% of their body weight can reduce adipose fat by up to 30%.⁶² Starting with an even more modest goal is realistic and worthwhile.

COCs are the primary treatment for contraception and regulation of menses in women with PCOS. COCs also offset the effect of estrogen on the endometrium and improve acne, hirsutism, and oligomenorrhea. Some studies suggest that COCs may aggravate IR, decrease glucose tolerance, and enhance CVD, but their ultimate effect on CVD and DM risks, even after decades of use, is unknown. Women who are obese, have PCOS, and are older are already at higher risk for DM and CVD; therefore, COC use in these patients must be carefully considered.

Use of metformin, an insulin sensitizer, in conjunction with TLC, improves the metabolic profile and is effective for weight loss, reducing visceral adiposity, and offsetting IR and DM,^60,63 which can help restore ovulatory cycles and regular menstruation. Metformin reduces IR and retards or prevents progression to DM in women with IGT.⁶⁴ This medication can reduce androgen secretion and raise sex hormone-binding globulin (SHBG) levels, thereby limiting T’s action.⁶⁵ Although no clear data show that metformin use reduces CVD risk, some evidence suggests that this agent protects against the adverse cardiovascular effects of IR and hyperinsulinemia.⁶⁶ 

The target dosage of metformin is 1500-2550 mg/day. Side effects are mainly gastrointestinal, and can be mitigated by using a sustained-released preparation and a low starting dosage of 250-500 mg once daily. The dosage is then increased over 4-6 weeks. Metformin users should be monitored for vitamin B12 levels and for signs/symptoms of vitamin B12 deficiency, including numbness, paresthesia, macroglossia, memory loss, behavioral changes, and pernicious anemia.⁶⁴ Use of metformin for prevention of pregnancy loss is off-label.⁶²

Clomiphene is the drug of choice to promote conception in women with PCOS.⁶² The usual regimen is 50 mg/day for 5 days, beginning on cycle day 3-5 following a spontaneous or progestin-induced bleed; the dosage can be increased by 50 mg/day to a maximum of 200 mg/day.⁶⁴ Treatment with gonadotropins often results in an overproduction of follicles, which may result in ovarian hyperstimulation syndrome and multiple pregnancies. Moreover, use of gonadotropins, though effective, is costly and time-consuming and requires intensive monitoring. A new surgical therapy, laparoscopic ovarian “drilling,” may avoid or reduce the need, or facilitate the use, of gonadotropins for inducing ovulation. The procedure can be done on an outpatient basis with less trauma and fewer postoperative adhesions. Many uncontrolled observational studies have claimed that this procedure is followed, at least temporarily, by a high rate of spontaneous postoperative ovulation and conception, and that subsequent pharmacologic ovulation induction becomes easier.⁶⁷

Postmenopause—PCOS was not described in postmenopausal women prior to 1996, in part because the condition of women with PCOS seemed to normalize, manifested by lower T levels and regular, ovulatory menses, as they approached menopause.¹ Early studies supported no increased morbidity/mortality for women with PCOS after menopause, despite ominous risk factors such as HTN, IGT, and obesity. More recent studies have shown different results when obesity was taken into account. Subtle metabolic alterations that accompany acanthosis nigricans signal a higher risk profile in obese postmenopausal women with PCOS.¹

Nearly all menopausal women experience increased total cholesterol (TC) and TG, decreased HDL-C, increased low-density lipoprotein cholesterol (LDL-C), increased IR, decreased insulin secretion, decreased insulin elimination, increased android fat distribution, impaired vascular function, increased Factor VII and fibrinogen, and reduced SHBG.²¹ These changes suggest a distinct menopausal metabolic syndrome related to decreased levels of estrogen.⁶⁸ Although these risk factors would seem to raise CVD risk, studies to date have not clearly demonstrated what role PCOS plays in CVD and DM.⁶⁹ Large multicenter trials of long-term cardiovascular outcomes are required to better define the incidence of CVD risk in women with PCOS. Regardless, women with PCOS should be screened for Met-S and its constellation of CVD risk factors.

Menopausal women experience a rise in pro-coagulant factors, inflammatory markers, and homocysteine levels,70 widened pulse pressure (ie, systolic BP rises whereas diastolic BP falls),²¹ and a weight gain of 1.2 pounds (0.55 kg) per year, with an increase in abdominal obesity.⁷¹ The increase in weight may have a greater influence than menopausal status on the decrease in insulin sensitivity.⁷² Whatever the cause, insulin metabolism changes after menopause, with a resultant decline in insulin sensitivity over time.⁷³ PCOS may accelerate development of a CVD risk profile or subclinical signs of atherosclerosis. Because 40%-60% of women with PCOS are obese, both the PCOS and the obesity may contribute to CVD pathology. In any event, obese women with PCOS suffer increased adverse changes after menopause, including endothelial dysfunction and inflammation,⁷⁴ an atherogenic serum lipid profile,¹⁵ increased coronary artery calcium,⁷⁵ non-alcoholic fatty liver disease and non-alcoholic fatty hepatitis,⁷⁶ and obstructive sleep apnea.⁷⁷ Distinguishing the particular contributions of obesity and of the inborn traits of PCOS is a high priority for understanding the syndrome and for reducing symptoms and chronic diseases in women with PCOS. 

Because many women with PCOS have co-existing Met-S, concern about CVD exists even if the relationship between the two syndromes is unclear. Obesity, raised serum TC, lowered HDL-C, elevated TG, HTN, IGT, a pro-inflammatory state with raised C-reactive protein, and a pro-thrombotic state are, individually and together, causes for concern.⁷⁸ The higher TG levels seen after menopause are correlated with obesity and IR.⁷⁹ Lean women with PCOS must be evaluated for metabolic problems as well.⁸⁰ They have IR intrinsic to PCOS, whereas obese women have IR from both intrinsic and adipose origins.⁸¹

Management. Menopausal women with PCOS experience the effects of lower estradiol levels (eg, hot flashes, night sweats, vaginal symptoms) in the same way as other women. For some women, these symptoms are mild, but for others, they interfere with quality of life.

Many menopause hormone therapy (HT) products, with different routes of delivery (eg, oral, transdermal, vaginal) are available. Transdermal and vaginal HT products do not undergo first-pass metabolism in the liver and are a better choice for women with PCOS and elevated TG. Vaginal products are an excellent choice for vaginal symptoms. The hormones used in these products are one-fourth as strong as those in COCs, but prospective users must be well screened and the risks/benefits thoroughly explored. Many women with PCOS are not good candidates for HT because of their cardiac risk factors. For women who “pass” the screening tests and wish to use HT, treatment should be initiated at or shortly after menopause, when potential beneficial cardiovascular effects are more likely to occur. Younger, healthier women who have not yet developed underlying coronary artery disease are the best candidates.^82,83 HT should be used at the lowest possible dosage for the shortest period of time. 

For many postmenopausal women, clinical management is no longer focused on controlling symptoms of PCOS but, rather, on controlling IGT and preventing CVD and DM. Metformin may be useful in this population because it will reduce IR and delay or prevent DM and reduce some CVD risk factors. After menopause, women may also need to use antihypertensive, antihyperlipidemic, and/or antidiabetic medications. Treatment is accompanied by education about TLC to offset chronic diseases, ways to avoid falls, and vision care.

Conclusion

PCOS is a serious disorder affecting many females, some from infancy through menopause. This multifaceted syndrome, characterized by oligo- or anovulation and hyperandrogenism, seriously interferes with reproductive capacity. Obesity, which affects at least 50% of women with PCOS, is implicated in problems of carbohydrate metabolism such as IGT and DM. Risks for CVD are likely related to PCOS, despite lack of data clearly establishing this link. Additional research is needed to clarify the etiology and PCOS definition so that clinical management can be further refined. NPs must identify PCOS in their patients as early as possible via appropriate screening. Once identified, management can be initiated to improve quality of life and reduce adverse consequences. Treatment requires more than COCs. Lifestyle interventions focusing on diet and exercise are coupled with medications to manage symptoms, restore fertility, and prevent long-term sequelae.

Mary Ellen Rousseau is a professor, clinical track, at Yale University School of Nursing in New Haven, Connecticut. The author states that she does not have a financial interest in or other relationship with any commercial product named in this article. 

References

1. Pasquali R, Gambineri A. Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age. Ann N Y Acad Sci. 2006;1092:158-174.
2. Barbieri R. Update in female reproduction: a life-cycle approach. J Clin Endocrinol Metab. 2008;93(7):2439-2446.
3. Essah P, Wickham E, Nestler J. The metabolic syndrome in polycystic ovary syndrome. Clin Obstet Gynecol. 2007;50(1):205-225.
4. Goodarzi M, Azziz R. Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab. 2006;20(2):193-205.
5. Stein I, Leventhal M. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29:181-191.
6. Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J (Clin Res Ed). 1986;293(6543):355-359.
7. Homburg R. Polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2008;22(2):261-274.
8. Rosenfield RL. Clinical review: Identifying children at risk for polycystic ovary syndrome. J Clin Endocrinol Metab. 2007;92(3):787-796.
9. Eden JA. The polycystic ovarian syndrome presenting as resistant acne successfully treated with cyproterone acetate. Med J Aust. 1991;155(10):677-680.
10. Legro RS. Polycystic ovary syndrome: the new millenium. Molec Cell Endocrinol. 2001;184(1-2):87-93.
11. Fraser IS, Kovacs, G. Current recommendations for the diagnostic evaluation and follow-up of patients presenting with symptomatic polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004;18(5):813-823.
12. Lobo R. Hirsutism in polycystic ovary syndrome: current concepts. Clin Obstet Gynecol. 1991;34(4):817-826.
13. Rexrode KM, Carey VJ, Hennekens CH, et al. Abdominal adiposity and coronary heart disease in women. JAMA. 1998;280(21):1843-1848.
14. Paoletti AM, Cagnacci A, Soldani R, et al. Evidence that an altered prolactin release is consequent to abnormal ovarian activity in polycystic ovary syndrome. Fertil Steril. 1995;64(6):1094-1098.
15. Valkenburg O, Steegers-Theunissen R, Smedts H, et al. A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: a case-control study. J Clin Endocrinol Metab. 2008;93(2):470-476.
16. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocrine Rev. 1997;18(6):774-800.
17. Fernandes AR, de Sá Rosa e Silva A, Romão G, et al. Insulin resistance in adolescents with menstrual irregularities. J Pediatr Adolesc Gynecol. 2005;18(4):269-274.
18. Stewart DR, Dombroski BA, Urbanek M, et al. Fine mapping of genetic susceptibility to polycystic ovary syndrome on chromosome 19p13.2 and tests for regulatory activity. J Clin Endocrinol Metab. 2006;91(10):4112-4117.
19. Azziz R. Androgen excess is the key element in polycystic ovary syndrome. Fertil Steril. 2003;80(2):252-254.
20. Goodarzi MO, Korenman SG. The importance of insulin resistance in polycystic ovary syndrome. Fertil Steril. 2003;80(2):255-258.
21. Kaaja R. Metabolic syndrome and the menopause. Menopause Int. 2008;14(1):21-25.
22. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(4):1929-1935.
23. Diamanti-Kandarakis E, Christakou C, Kandarakis H. Polycystic ovarian syndrome: the commonest cause of hyperandrogenemia in women as a risk factor for metabolic syndrome. Minerva Endocrinol. 2007;32(1):35-47.
24. Zawadski J, Dunaif A, eds. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, Merriam G, eds. Polycystic Ovary Syndrome. Cambridge, MA: Blackwell Scientific Publications; 1992. 
25. 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(1):19-25.
26. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91(2):456-488.
27. Azziz R, Carmina E, Dewailly D, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006;91(11):4237-4245.
28. Lane D. Polycystic ovary syndrome and its differential diagnosis. Obstet Gynecol Survey. 2006;61(2):125-135.
29. Speroff L. Polycystic ovarian syndrome and insulin resistance. 2009. Personal communication.
30. Shaw L, Elton S. Polycystic ovary syndrome: a transgenerational evolutionary adaptation. BJOG. 2008;115(2):144-148.
31. Hart R, Hickey M, Franks S. Definitions, prevalence and symptoms of polycystic ovaries and polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004;18(5):671-683.
32. Legro R, Kunselman A, Demers L, et al. Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(5):2134-2138.
33. Sam S, Legro R, Essah P, et al. Evidence for metabolic and reproductive phenotypes in mothers of women with polycystic ovary syndrome. Proc Natl Acad Sci U S A. 2006;103(18):7030-7035.
34. Sam S, Coviello AD, Sung YA, et al. Metabolic phenotype in the brothers of women with polycystic ovary syndrome. Diabetes Care. 2008;31(6):1237-1241.
35. Recabarren SE, Sir-Petermann T, Rios R, et al. Pituitary and testicular function in sons of women with polycystic ovary syndrome from infancy to adulthood. J Clin Endocrinol Metab. 2008;93(9):3318-3324.
36. Colilla S, Cox N, Ehrmann D. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. J Clin Endocrinol Metab. 2001;86(5):2027-2031.
37. Ibanez L, Potau N, Francois I, de Zegher F. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab. 1998;83(10):3558-3562.
38. Cresswell JL, Barker DJ, Osmond C, et al. Fetal growth, length of gestation, and polycystic ovaries in adult life. Lancet. 1997;350(9085):1131-1135.
39. Hales C, Barker D. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35(7):595-601.
40. Adair L, Prentice A. A critical evaluation of the fetal origins hypothesis and its implications for developing countries. J Nutr. 2004;134(1):191-193.
41. Neel J. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet. 1962;14:353-362.
42. Barker D, Gluckman P, Godfrey K, et al. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993;341(8850):938-941.
43. Ibanez L, Ong K, Dunger D, de Zegher F. Early development of adiposity and insulin resistance after catch-up weight gain in small-for-gestational-age children. J Clin Endocrinol Metab. 2006;91(6):2153-2158.
44. Hovi P, Andersson S, Eriksson J, et al. Glucose regulation in young adults with very low birth weight. N Engl J Med. 2007;356(20):2053-2063.
45. Hague W, Adams J, Reeders S, et al. Familial polycystic ovaries: a genetic disease? Clin Endocrinol. 1988;29(6):593-605.
46. Buggs C, Rosenfield R. Polycystic ovary syndrome in adolescence. Endocrinol Metab Clin North Am. 2005;34(3):677-705.
47. Warren-Ulanch J, Arslanian S. Treatment of PCOS in adolescence. Best Pract Res Clin Endocrinol Metab. 2006;20(2):311-330.
48. Diamanti-Kandarakis E. Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. Expert Rev Mol Med. 2008;10(2):e3.
49. Ibanez L, Valls C, Potau N, et al. Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism after precocious pubarche. J Clin Endocrinol Metab. 2000;85(10):3526-3530.
50. Kaplowitz P, Oberfield S. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Pediatrics. 1999;104(4 pt 1):936-941.
51. Brito V, Latronico A, Cukier P, et al. Factors determining normal adult height in girls with gonadotropin-dependent precocious puberty treated with depot gonadotropin-releasing hormone analogs. J Clin Endocrinol Metab. 2008;93(7):2662-2669.
52. Ford E, Giles W, Dietz W. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287(3):356-359.
53. Leibel NI, Baumann EE, Kocherginsky M, Rosenfield RL. Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. J Clin Endocrinol Metab. 2006;91(4):1275-1283.
54. Lee S, Bacha F, Arslanian S. Waist circumference, blood pressure, and lipid components of the metabolic syndrome. J Pediatr. 2006;149(6):809-816.
55. Avvad C, Holeuwerger R, Silva V, et al. Menstrual irregularity in the first postmenarchal years: an early clinical sign of polycystic ovary syndrome in adolescence. Gynecol Endocrinol. 2001;15(3):170-177.
56. van Hooff M, Voorhorst F, Kaptein M, et al. Relationship of the menstrual cycle pattern in 14-17 year old adolescents with gynaecological age, body mass index and historical parameters. Hum Reprod. 1998;13(8):2252-2260.
57. Silfen M, Denburg M, Manibo A, et al. Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents. J Clin Endocrinol Metab. 2003;88(10):4682-4688.
58. Goldzieher J, Axelrod L. Clinical and biochemical features of polycystic ovarian disease. Fertil Steril. 1963;14:631-653.
59. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Cardiol Rev. 2005;13(6):322-327.
60. Salley K, Wickham E, Cheang K, et al. Glucose intolerance in polycystic ovary syndrome--a position statement of the Androgen Excess Society. J Clin Endocrinol Metab. 2007 92(12):4546-4556.
61. Essah P, Nestler J. Metabolic syndrome in women with polycystic ovary syndrome. Fertil Steril. 2006;86(suppl 1):S18-S19.
62. Mathur R, Alexander C, Yano J, et al. Use of metformin in polycystic ovary syndrome. Am J Obstet Gynecol. 2008;199(6):596-609.
63. Palomba S, Falbo A, Zullo F, Orio F Jr. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;30(1):1-50.
64. Nestler J. Metformin in the treatment of infertility in polycystic ovarian syndrome: an alternative perspective. Fertil Steril. 2008;90(1):14-16.
65. Utiger R. Insulin and the polycystic ovary syndrome. N Engl J Med. 1996;335(9):657-658.
66. Nestler J, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72(1):83-89.
67. Polson D, Adams J, Wadsworth J, Franks S. Polycystic ovaries--a common finding in normal women. Lancet. 1988;1(8590):870-872.
68. Spencer C, Godsland I, Stevenson J. Is there a menopausal metabolic syndrome? Gynecol Endocrinol. 1997;11(5):341-355.
69. Corbett SJ, McMichael AJ, Prentice AM. Type 2 diabetes, cardiovascular disease, and the evolutionary paradox of the polycystic ovary syndrome: a fertility first hypothesis. Am J Hum Biol. 2009;21(5):587-598.
70. Rees M, Purdie M, David W, eds. Management of the Menopause: The Handbook. 4th ed. London, UK: London Royal Society of Medicine Press; 2006.
71. Toth M, Sites C, Eltabbakh G, Poehlman E. Effect of menopausal status on body composition and abdominal fat distribution. Int J Obes Relat Metab Disord. 2000;24(2):226-231.
72. Guthrie J, Ball M, Dudley E, et al. Impaired fasting glycaemia in middle-aged women: a prospective study. Int J Obes Relat Metab Disord. 2001;25(5):646-651.
73. Walton C, Godsland I, Proudler A, et al. The effects of the menopause on insulin sensitivity, secretion and elimination in non-obese, healthy women. Eur J Clin Invest. 1993;23(8):466-473.
74. Heutling D, Schulz H, Nickel, I. et al. Asymmetrical dimethylarginine, inflammatory and metabolic parameters in women with polycystic ovary syndrome before and after metformin treatment. J Clin Endocrinol Metab. 2008;93(1):82-90.
75. Shroff R, Kerchner A, Maifeld M, et al. Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab. 2007;92(12):4609-4614.
76. Setji T, Holland N, Sanders L, et al. Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(5):1741-1747.
77. Tasali E, Van Cauter E, Hoffman L, Ehrmann D. Impact of obstructive sleep apnea on insulin resistance and glucose tolerance in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93(10):3878-3884.
78. Grundy SM, Hansen B, Smith SC Jr, et al. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Arterioscler Thromb Vasc Biol. 2004;24(2):e19-e24.
79. Norman R, Masters S, Hague W, et al. Metabolic approaches to the subclassification of polycystic ovary syndrome. Fertil Steril. 1995;63(2):329-335.
80. Dokras A, Bochner M, Hollinrake E, et al. Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol. 2005;106(1):131-137.
81. Essah PA, Wickham EP, Nestler JE. The metabolic syndrome in polycystic ovary syndrome. Clin Obstet Gynecol. 2007;50(1):205-225.
82. Schnatz P. Hormonal therapy: does it increase or decrease cardiovascular risk? Obstet Gynecol Surv. 2006;61(10):673-681.
83. Barrett-Connor E. Hormones and heart disease in women: the timing hypothesis. Am J Epidemiol. 2007;166(5):506-510.