Abstract
Polycystic ovary syndrome (PCOS) is one of the most frequently encountered endocrine disorders occurring in women of reproductive age. Clinically, a patient usually presents with menstrual irregularities, infertility, and hirsutism. If not treated properly, a patient is at risk for type 2 diabetes, cardiovascular disease, and hyperestrogen-related cancers. The hallmark endocrine disorders of this syndrome are hyperandrogenism and hyperinsulinemia. Great controversy exists as to which state precedes the other. There also appears to be a defect in the hypothalamic-pituitary-adrenal (HPA) axis in patients presenting with polycystic ovary syndrome. Research consistently demonstrates that the first line of treatment for this condition is weight loss. Weight loss and dietary changes appear to affect all parameters of hormonal fluctuation. Due to the vast array of side effects associated with many pharmaceutical agents typically prescribed to treat PCOS, natural therapeutics including nutrient supplementation and botanicals may be a less invasive and equally effective approach. Due to the seriousness of this syndrome when left untreated, prompt evaluation and treatment is essential.
(Altern Med Rev 2001;6(3):272-292)
Introduction
Polycystic ovary syndrome (PCOS) is a prevalent and frequently encountered endocrine disorder.[1] It has been suggested that this condition occurs in as many as 4-10 percent of women of reproductive age,[2] with onset manifesting as early as puberty.[3] Because of the diversity of clinical and metabolic findings in PCOS, there has been great debate as to whether it represents a single disorder or multiple associated pathologic conditions. PCOS is primarily characterized by hyperandrogenism, insulin resistance, and chronic anovulation.[4] Hyperandrogenism and insulin were linked as early as 1921, when Achard and Thiers published a classic description of bearded women with diabetes.[5] However, polycystic ovary syndrome was not described until 1935, when Stein and Leventhal described the syndrome as having pathognomonic ovarian findings and the clinical triad of hirsutism, amenorrhea, and obesity.[6] Today, a patient usually presents clinically with concerns regarding menstrual irregularities, infertility, and hirsutism. The syndrome is also associated with dyslipidemia and acanthosis nigricans,[7] and may increase the risk for cardiovascular disease[8] and hyperestrogen-related cancers such as endometrial[9] and breast[10] cancers. During the reproductive years, PCOS is associated with significant reproductive morbidity, including infertility, abnormal uterine bleeding, miscarriage, and other complications of pregnancy.[11]
PCOS usually begins in adolescence, and it is difficult to predict whether the symptoms of the syndrome will self correct or persist into adulthood. Up to 50 percent of women affected with PCOS are obese, a condition that has been found to increase the magnitude of underlying insulin resistance.[12] Obesity tends to be less of a problem in women with PCOS in the adolescent population.[13] However, both the adolescent and middle age groups tend to have android body types, with waist-to-hip ratios greater than 0.8, even in the presence of normal body mass index.[12] Obesity has also been linked to increased androgen production and hirsutism.[14] Because of the wide range of symptoms and maladies associated with PCOS, thorough evaluation and diagnosis is essential to prevent further pathology.
Pathophysiology
The underlying defect in polycystic ovaries remains unknown; however, there is growing consensus that the key features are androgen excess, insulin resistance, and abnormal gonadotropin dynamics. The largest question is whether the hyperinsulinemic state stimulates excess ovarian androgen production, or whether a chronic hyperandrogenic state promotes insulin resistance. There is also growing evidence of a link between chronic stress situations and multiple hormonal imbalances.
PCOS has clearly proven itself to be a disorder of excess physiological response to androgens. Once androgens reach target cells they must interact with the androgen receptor, which is encoded by a gene on the X chromosome. Testosterone is the most important circulating androgen. Approximately one-half of a woman's serum testosterone is derived from peripheral conversion of secreted androstenedione, while the other half is derived from direct glandular secretion. The ovaries and the adrenal glands contribute equally to testosterone production in women;[15] however, in PCOS the main source of androgens is thought to come from the ovaries. Dysregulation of cytochrome p450c 17, the androgen-forming enzyme in both the adrenals and the ovaries, may be the central pathogenic mechanism underlying hyperandrogenism in PCOS. In the presence of 5-alpha-reductase, testosterone is convened within the cell to the more potent androgen dihydrotestosterone. Excess 5-alphareductase activity in the skin determines the presence or absence of hirsutism.[16] Additionally, estrone (E1) levels are increased as a result of peripheral conversion of androstenedione. Estradiol (E2) levels are normal in PCOS because they predominately occur during the follicular phase, which is not abnormal in this condition.[17] This results in a chronic hyperestrogenic state with the reversal of the E1:E2 ratio, predisposing patients to a number of further health complications.
Normally less than three percent of testosterone circulates freely in the serum. Most circulating androgens are bound, primarily to sex hormone-binding globulin (SHBG). When bound to SHBG, the hormone is considered biologically inactive. Any condition that decreases the levels of SHBG or other binding proteins can lead to a relative excess of circulating androgens. In patients with hirsutism, the major conditions that are linked with decreased SHBG levels are PCOS and obesity, independently.[18]
Androgens may both directly and indirectly result in alterations in glucose metabolism, ultimately causing a hyperinsulinemic state (Figure 1). Androgens may directly inhibit peripheral and hepatic insulin action. A study by Ciaraldi et al found that insulin receptor binding and kinase activity were intact in adipocytes of women with PCOS, although they exhibited marked decrease in insulin sensitivity for glucose transport stimulation.[19] The study concluded there was a post-binding defect present, which was probably related to the increasing androgen levels in PCOS women. This group suggested that testosterone could induce insulin resistance in these women by reducing the number and efficacy of glucose transport proteins, specifically the type-4 glucose transporter (GLUT-4). GLUT-4 appears to be responsible for the insulin-related uptake of glucose in muscle and fat.
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It has also been shown that women with central obesity, the type most commonly seen with PCOS, have higher free androgen levels and exhibit significantly higher levels of insulin insensitivity compared to weight-matched controls.[20] Androgens and increased free fatty acids (FFAs), common in central obesity, inhibit hepatic insulin excretion, resulting in hyperinsulinemia and insulin resistance.[21] Testosterone is known to facilitate lipolysis, providing increased FFA concentrations.[22] Even more important to this mechanism is the fact that elevated FFA levels have been shown to inhibit insulin-stimulated glucose uptake in skeletal muscle, a condition that defines insulin resistance.[23] A study by Nagamani et al examined women with ovarian hyperandrogenism and hyperinsulinemia. Following bilateral oophorectomy, hyperandrogenism was eliminated without improvement in insulin resistance.[24] This could in part be due to other related factors such as diet and family history.
Insulin resistance and compensatory hyperinsulinemia are characteristic metabolic disturbances of many, but not all, women with PCOS. Hyperinsulinemia may be central to the pathogenesis of the syndrome for some women, since it can induce hyperandrogenism and anovulation.[25] Studies have demonstrated, both in vivo and in vitro, that hyperinsulinemia stimulates ovarian androgen production and decreases the synthesis of SHBG by the liver.[26] Hyperinsulinemia in women with PCOS has proven to be associated with a higher frequency of menstrual abnormalities than in normoinsulinemic women with PCOS.[27] It has also been shown that chronic hyperandrogenism and hyperinsulinemia affect the secretion of gonadotropins in favor of increased luteinizing hormone (LH), which contributes to the mechanism of anovulation.[28]
Insulin resistance in at least 50 percent of women with PCOS appears to be related to excessive serine phosphorylation of the insulin receptor. A factor that is extrinsic to the insulin receptor, which is thought to be a serine/threonine kinase, appears to cause the abnormality. Serine phosphorylation modulates the activity of the key regulatory enzyme of androgen biosynthesis, p450c 17. Therefore, it is possible a single defect produces both insulin resistance and hyperandrogenism in some PCOS women.[29]
Reports conflict regarding the presence of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in women with PCOS. Anovulation is associated with disturbances in the feedback from the ovarian steroid hormones to the hypothalamus and pituitary, resulting in disturbances in the pulsatility of gonadotropin releasing hormone (GnRH) release. Gonadotropin-secretory changes, with a characteristic increase in LH relative to follicle-stimulating hormone (FSH) release, have long been recognized in PCOS.[30]It has also been suggested that the elevated concentrations of LH are due to an abnormal feedback by estrogen[31] and that the high concentrations of LH in PCOS are detrimental to follicular growth.[30]
One hypothesis suggests PCOS is caused by insufficient central [Beta]-endorphin inhibition of GnRH, thus maintaining elevated [Beta]-endorphin levels. This hypothesis is supported by studies showing [Beta]-endorphin exerts tonic inhibitory control on the GnRH pulse generator and on pituitary LH release.[32,33] The involvement of [Beta]-endorphins in PCOS is also supported by the finding that elevated [Beta]-endorphin levels in plasma are related to hyperinsulinemia. Interestingly, [Beta]-endorphin levels are also elevated following stress.[11] A second hypothesis was explored in rat studies in which experimentally-induced PCOS yielded increased levels of norepinephrine and decreased numbers of [Beta]-adrenoreceptors in the ovaries.[34] Together this would imply that PCOS is associated with elevated sympathetic tone in the ovaries, resulting in steroidal hyperresponsiveness.
A study performed by Waldstreicher et al measured frequent (every 10 minutes) and prolonged (12-24 hours) serial blood samples which revealed a significant increase in the frequency and amplitude of LH release with normal FSH release in PCOS.[35] The increased LH pulse frequency reflects an increase in GnRH release and suggests the presence of a hypothalamic defect.[36] Ovulatory women with the polycystic morphology can have increased LH/FSH ratios; however, a single blood sample can fail to detect an increased ratio. Because of a lack of specificity, it is recommended that this ratio not be used as a diagnostic criteria.[29]
It has been demonstrated that women with PCOS have significantly higher adrenocorticotropic hormone (ACTH) and cortisol response to the administration of corticotropin-releasing hormone (CRH).[37] This suggests hyperfunction of the HPA axis as demonstrated by patients' response to Naloxone administration.[38] It is suggested that increased activity at this level could be central in origin, possibly secondary to altered sensitivity to the opioid system at the pituitary level and/or to increased opioid tone. Neuroendocrine alterations may also lead to increased sensitivity of ACTH-secreting cells to CRH.[39] It has also been demonstrated that only obese women with PCOS show HPA-axis hyperactivity in response to opioid blockade, in contrast to lean women with PCOS and lean and obese control subjects.[40]
Adrenal insufficiency may be more common in the pathogenesis of PCOS than was previously thought. It is believed that women with PCOS have a tendency toward high cortisol levels; however, when placed in a chronic stress situation, adrenal reserves are depleted. When an individual is in a state of low adrenal reserve, in the absence of significant stress, the adrenal glands are still able to produce sufficient hormones to maintain a somewhat normal state of health. However, when presented with an acute or chronic stress, there is an increased demand for adrenocortical hormones. Symptoms can range from fatigue to complete collapse, and resulting disease conditions may include menstrual irregularities, type 2 diabetes mellitus, hypertension, and autoimmune diseases.[41] With this in mind, we can speculate that individuals with chronic stress may be predisposed to conditions such as PCOS. Psychological stress appears to be more prevalent in women with PCOS.[42,43]
A study of women with PCOS evaluated adrenal androgen secretion using the ACTH stimulation test following bilateral ovarian wedge resection to surgically induce ovulation. Adrenal androgen secretions were evaluated before and again six months after surgery. The PCOS group was compared to a group of women with regular ovulatory cycles, and matched for age and body mass index. Previous to the surgery, the PCOS group showed higher basal levels of testosterone, androstenedione, 17-hydroxyprogesterone (17-OHP), and LH, with decreased SHBG. Following wedge resection, PCOS subjects exhibited significant reduction in their mean levels of testosterone, androstenedione, 17-OHP, LH, as well as an increase in SHBG. No differences were found for baseline levels of DHEA in any of the subjects.[44] The increased response of androstenedione to ACTH stimulation seems to indicate the hyperandrogen response is adrenal in origin and should be further evaluated with regard to possible stress-related conditions. It also seems likely that adrenal hyperandrogenism is maintaining the ovulatory dysfunction in some patients with PCOS. In patients with PCOS and excessive adrenal androgen secretion, treatment with glucocorticoids established menstrual regularity in only 30-66 percent of patients.[45] Previous investigators have found DHEA levels to be elevated in 70-75 percent of patients with PROS.[46]
A study of adolescent women with PCOS found ovarian volume and ovaries with a polycystic appearance had a positive correlation with DHEA, androstenedione, and testosterone levels, supporting the view that hormone dysregulation may be an important factor.[47] Adolescents with PCOS typically present with oligomenorrhea and marked hyperandrogenism without hyperinsulinemia. This supports the notion that hyperandrogenism precedes hyperinsulinemia.
Diagnostic Criteria
PCOS is known to be associated with reproductive morbidity and increased risk for endometrial and breast cancer; therefore, early diagnosis is extremely important. PCOS is thought to be linked to metabolic and cardiovascular risks, making preventive therapy crucial. A thorough history must be taken, including the timing and chronological expression of symptoms. The onset of pubertal development and menstrual regularity is important, as any evidence of precocious puberty is often associated with androgen hyperactivity.[16] Menstrual irregularities range from symptoms of amenorrhea (cessation of menses), to oligomenorrhea (infrequent menses), to menorrhagia (excessive duration or amount of bleeding).[48,49] Family history is important in establishing links between onset of puberty, menstrual irregularities, diabetes, and familial patterns of hair growth. Studies show that PCOS has a genetic component, most likely with an autosomal dominant mode of transmission.[50]
Physical examination should focus on establishing the presence and extent of hirsute symptoms, such as acne and excessive hair growth. Hip-to-waist ratios and body mass index are also important parameters to measure. On gynecologic exam, palpation of the ovaries should be performed to assess for cysts. Additionally, a cardiovascular evaluation should be made if the patient is in her third decade or beyond or has high blood pressure.
In 1990, the National Institutes of Health formed a group to investigate PCOS. Even though no consensus was reached regarding the name of this disorder, which remains controversial to date, diagnostic criteria were determined.[51] The consensus was that women who present with hyperandrogenism and chronic anovulation, in the absence of congenital adrenal disorders, Cushing's syndrome, hyperprolactinemia, or tumors should be diagnosed with PCOS.[52]
Excess androgen production is the most common trigger for hirsutism, which appears on physical exam as excessive, coarse hair in an abnormal pattern.[53] This definition highlights the abnormal distribution of excess hair growth, such as facial, chest, or upper abdominal hair. Virilization refers to the concurrent presentation of hirsutism with a broad range of signs suggestive of androgen excess, such as acne, fronto-temporal balding, deepening of the voice, a decrease in breast size, clitoral hypertrophy, increased muscle mass, and amenorrhea or oligomenorrhea. Hirsutism and virilization are closely linked; however, hirsutism often precedes virilization if left untreated. Although the source of androgens can be exogenous, it is most commonly endogenous as a result of adrenal and ovarian production.[16] Hirsutism may develop peripubertally or during adolescence, or it may be absent until the third decade of life.[52] Some women with PCOS never develop signs of androgen excess because of genetic differences in receptor number or tissue sensitivity.[42]
Initial laboratory testing for the assessment of hirsutism should include total and/or free testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone measurements. Normal values for serum androgens are listed in Table 1. If a patient is also oligomenorrheic, LH, FSH, prolactin, and thyroid-stimulating hormone tests may be useful as well. Serum testosterone level is the best marker for ovarian hyperandrogenism, and DHEAS is the best adrenal marker. It is recommended that these levels be measured. Free testosterone provides a better diagnostic yield for ovarian hyperandrogenism because levels of SHBG are decreased thus increasing free hormone levels. Clinical assays used to test this measure vary considerably, perhaps affecting reliability.
Table 1. Relative Risks of Cardiovascular Events According to Baseline
Plasma Levels of Markers of Inflammation and Lipids
Se