Polycystic Ovary Syndrome - technical article
Introduction
Polycystic ovary syndrome (PCOS) refers to a complex, multidimensional disorder resulting in defects in reproduction and metabolism. Although one of the primary characteristic of PCOS is the presence of multiple cysts on the ovaries, the complexity of the syndrome is reflected in the wide range of its clinical manifestations, most notably insulin resistance, obesity, irregular menses, and signs of hyperandrogenism, such as hirsutism and acne.
Diagnostic Criteria
In 1990, a conference on PCOS sponsored by the National Institutes of Health led to diagnostic criteria based on a majority opinion of conference participants [ 1 ] . The criteria included hyperandrogenism and/or hyperandrogenemia, chronic anovulation, and exclusion of other known disorders. In 2003, a PCOS consensus workshop in Rotterdam sponsored by the European Society of Human Reproduction and Embryology (ESHRE)/American Society of Reproductive Medicine (ASRM) revised the diagnostic criteria for PCOS [ 2 ] . The revised criteria state that PCOS remains a diagnosis of exclusion, but that two out of the following three criteria must be present: (1)
- oligo- or anovulation, (2)
- hyperandrogenism and/or hyperandrogenemia, and (3)
- polycystic ovaries.
A polycystic ovary is defined as having 12 or more follicles in one ovary measuring 2–9 mm in diameter, and/ or increased ovarian volume of greater than 10 mL, which is the maximum size of a normal ovary [ 3 ] (Fig. 8.1 ). Administration of oral contraceptive pills and the presence of follicles >10 mm modify ovarian morphology; thus, the definition of a polycystic ovary does not apply to these clinical scenarios.
The differential diagnosis should include other causes of hyperandrogenism and menstrual dysfunction such as nonclassical congenital adrenal hyperplasia (CAH), hypothalamic amenorrhea, Cushing’s syndrome and disease, hyperprolactinemia, thyroid disease, acromegaly, and androgen- secreting neoplasms of the ovary or adrenal gland.
Prevalence
The prevalence of PCOS is estimated to be 4–12 % of reproductive- age women. The largest US study on PCOS prevalence was published in 1998 [ 4 ] . Out of 277 women included in the study, 4.0 % had PCOS as defined by the 1990 NIH criteria. The prevalence was 4.7 % for white women and 3.4 % for black women. The inclusion of polycystic ovaries in the 2003 Rotterdam criteria calls for reevaluation of the prevalence of PCOS, as 21–23 % of normal women have polycystic-appearing ovaries on ultrasound [ 3 ].
Clinical Presentation
Hyperandrogenism
Clinical manifestations of hyperandrogenemia include hirsutism, acne, and male pattern alopecia. Hirsutism is defined as the growth of coarse, pigmented hairs in androgen-dependent areas such as the face, chest, back, and lower abdomen. Approximately 80 % of hirsute patients will have PCOS [ 5 ] . The modified Ferriman-Gallwey scoring system can be used for clinical assessment of hirsutism. This system, which was originally used in the United Kingdom for a population of presumably Caucasian women, scores hair growth in nine body areas from 0 (absence of terminal hairs) to 4 (extensive terminal hair growth) [ 6 ]. Other hyperandrogenic manifestations commonly found in PCOS patients include acne and alopecia [ 7, 8 ] . Acne is a result of androgen stimulation of the pilosebaceous unit with increased skin oiliness [ 7 ] .
Obesity
Obesity is very common in PCOS, with the android pattern present in approximately 44 % of women with PCOS [ 9 ] . This central obesity is more characteristic of PCOS, as these patients have an increased waist-to-hip ratio compared to obese women without PCOS [ 10 ] . Hyperinsulinemia may stimulate central adiposity, which, in turn, exacerbates underlying or latent insulin resistance [ 11 ] .
Insulin Resistance, Diabetes, and Acanthosis Nigricans
Insulin resistance and diabetes are important health concerns commonly seen in association with polycystic ovarian syndrome and will be discussed at length later in this article. Acanthosis nigricans is a dermatological condition of hyperkeratosis and increased skin pigmentation with raised, symmetrical, darkened, velvety plaques that commonly appear on the nape of the neck. It can also be found in the axilla, groin, and other intertriginous areas of the body. Elevated insulin has a mitogenic effect on basal cells of the epidermis, making acanthosis nigricans a relatively specific clinical marker of insulin resistance [ 12 ].
Irregular Menses and Infertility
Some of the menstrual abnormalities seen with chronic anovulation include secondary amenorrhea, oligomenorrhea, and dysfunctional uterine bleeding. Menarche typically begins at a normal or early age, but the menstrual irregularities often seen in adolescents may never resolve for the PCOS patient. The irregular menses may be masked in PCOS patients if they are on oral contraceptives. PCOS is the most common cause of anovulatory infertility, which often serves as the impetus for the patient to seek medical attention. Patients may report false-positive urinary ovulation predictor tests due to chronic elevation in luteinizing hormone (LH).
Miscarriage
The risk of a first-trimester spontaneous abortion is reported to be significantly higher for patients with PCOS. The spontaneous abortion rate in PCOS is reported to be 30 % [ 13 ] . In comparison, retrospective studies find the risk of spontaneous abortion to be 5–14 % for normal women [ 14, 15 ] . Of patients with recurrent miscarriage, 36–82 % have polycystic ovaries [ 13, 16, 17 ] .
Several explanations have been offered. For example, Homburg et al. demonstrated that high concentrations of LH during the follicular phase in women with polycystic ovaries have a deleterious effect on rates of conception and are associated with early pregnancy loss [ 18 ] .
Pathogenesis
Altered Gonadotropin Secretion
One of the well-described features of PCOS is an increase in LH and relative decrease in follicle-stimulating hormone (FSH) [ 19 ] . The relative decrease in FSH is the chief cause of anovulation. The pulsatile secretion of LH from the pituitary is increased in amplitude and frequency [ 20 ] . In addition, the pituitary has a greater LH response to gonadotropin-releasing hormone (GnRH) compared with normal women [ 20, 21 ] .
The pulsatile secretion of GnRH cannot be studied in humans, so it must be inferred by detecting peripheral LH patterns. A study of PCOS women by Berga et al. found increased pulse frequency and amplitude for LH and a (alpha)-subunit, providing evidence for aberrant increases in GnRH pulse frequency (Fig. 8.2 ) [ 20 ] . Elevated LH is not caused by altered pituitary sensitivity to GnRH, as GnRH receptor blockade resulted in similar LH decreases in PCOS and normal women [ 22 ] . These findings suggest a derangement of the hypothalamic-pituitary axis, which appears to play a major role, because many of the cardinal features of PCOS can be traced to alterations in gonadotropins.
Neuroanatomical Considerations
The GnRH pulse generator refers to the synchronized pulsatile secretion of GnRH from neurons that are widely distributed in the medial basal hypothalamus. Knobil and associates conducted experiments with the Rhesus monkey to establish that the GnRH system exhibits rhythmic electrical behavior in the arcuate nucleus of the medial basal hypothalamus [ 23 ] . There was remarkable synchrony between pulses of GnRH in the portal blood and LH pulses in peripheral blood. This phenomenon was later studied in isolated human medial basal hypothalamus, where GnRH pulses were found to occur at a frequency of 60–100 min [ 24 ] .
The secretion of GnRH into the portal vasculature also appears to be regulated by dynamic remodeling of GnRH neurovascular junctions. Morphological plasticity of the median eminence during the menstrual cycle has been demonstrated, where the maximal number of GnRH neuro-vasculature junctions are found during the LH surge [ 25 ] .
GnRH Neuroregulation in PCOS
The GnRH pulse generator in PCOS patients is intrinsically faster, and the frequency is less likely to be suppressed with continuous estrogen and progesterone treatment [ 26 ] .
Increased central adrenergic tone has been implicated as a cause of the aberrations of GnRH and gonadotropin secretion in PCOS. One possible mechanism is the increase in local blood flow and permeability of the portal vascular system, permitting the entry of increased amounts of GnRH [ 27 ] . Dopamine injection into the third ventricle led to a rapid increase in GnRH and prolactin inhibitory factor in portal blood, suggesting dopamine-mediated regulation of GnRH and prolactin inhibitory factor [ 28 ] . The identification of b (beta)-1-adrenergic and D1-dopaminergic receptors on GT-1 GnRH neurons provides a mechanism by which norepinephrine and dopamine could regulate gonadotropin release via direct synapses on GnRH neurons [ 29 ] .
The role of insulin-like growth factor 1 (IGF-1) in modulation of GnRH cells has also been investigated. IGF-1 regulates growth, differentiation, survival, and reproductive function. The IGF receptor is a tyrosine kinase receptor located in the periphery and CNS, including the median eminence [ 30 ] . In PCOS women, an increased ratio of IGF-1 to their binding proteins correlated significantly with increased concentrations of circulating LH [ 21 ] . These findings suggest that IGF-1 can modulate GnRH neurons by inducing gene expression, resulting in more circulating LH.
Hyperandrogenemia
Circulating androgens are elevated in PCOS, with contributions from the ovary and adrenal glands. The elevated androgens can only be partially suppressed with combined oral contraceptive (COC) therapy. Daniels and Berga treated PCOS women with 3 weeks of COCs and found that androstenedione levels remained significantly higher compared to treated controls [ 26 ] . Pulse frequency of LH was suppressed in both PCOS women and controls, but the frequency remained signi fi cantly higher in PCOS patients (Fig. 8.3 ). This suggests there is reduced sensitivity of the GnRH pulse generator to suppression by sex steroids. The authors also suggest that GnRH drive in PCOS women may be intrinsically and irreversibly faster than in eumenorrheic women.
Theca Cell Function
Ovarian hyperandrogenism is driven by LH acting on theca cells, and the effect is ampli fi ed by the increased sensitivity of PCOS theca cells to LH [ 31 ] . Hyperandrogenism may also result from dysregulation of the androgen-producing enzyme P450c17, which has 17 a (alpha)-hydroxylase and 17,20-lyase activities. In contrast, in vivo studies do not find significant increases in androgen secretion in women with PCOS or normal women, despite considerable increases in insulin levels. A role for insulin is strongly suggested by the observation that reduction of hyperinsulinemia is associated with decreases of serum androgens. Treatment of PCOS patients with metformin, which reduces hepatic glucose production and secondarily lowers insulin, has been shown to decrease levels of testosterone, DHEAS, and androstenedione [ 32 ] .
Adrenal Function
Excess adrenal androgen production is seen in PCOS women, with a 48–64 % increase in DHEAS and 11 b (beta)-hydroxyandrostenedione. The underlying cause of elevated adrenal androgens is yet to be elucidated, but PCOS women do not have increased adrenocorticotropic hormone (ACTH) levels [ 33 ] . Increased adrenal androgen production in PCOS is likely caused by either altered adrenal responsiveness to ACTH or abnormal adrenal stimulation by factors other than ACTH.
Anovulation
The cause of anovulation in PCOS patients has yet to be clarified. However, several observations in granulosa function have been described that may give insight into this process.
Granulosa Cell Function
FSH levels are characteristically low in PCOS women, resulting in arrested follicular development. Insufficient granulosa cell aromatase activity was the basis of earlier studies that tried to explain poor follicular development, as follicular fluid estradiol concentrations were thought to be low. To the contrary, more recent studies found that PCOS granulosa cells are hyperresponsive to FSH in vitro, and estradiol concentrations from PCO follicles and normal follicles are no different [ 34 ] . A dose response study in PCOS women demonstrated a significantly greater capacity for estradiol production in response to recombinant human FSH compared with normal women [ 35 ] . The incremental response of serum estradiol was almost 2 times greater and considerably accelerated compared with that found in normal women.
Insulin Resistance
Although 50–70 % of PCOS patients have insulin resistance [ 36 ] , it is not one of the diagnostic criteria of PCOS. The topic deservedly receives much attention, as many of the clinical signs and symptoms of PCOS may be attributed to excess insulin exposure. The precise molecular basis for insulin resistance is unknown, but it appears to be a postreceptor defect [ 37 ] . There is tissue specificity of insulin resistance in PCOS: muscle and adipose tissue are resistant, while the ovaries, adrenals, liver, skin, and hair remain sensitive. The resistance to insulin in skeletal muscle and adipose tissue leads to a metabolic compromise of insulin function and glucose homeostasis, but there is preservation of the mitogenic and steroidogenic function in other tissues. The effect of hyperinsulinemia on the sensitive organs results in downstream effects seen in PCOS, such as hirsutism [ 5 ] , acanthosis nigricans [ 12 ] , obesity [ 11 ] , stimulation of androgen synthesis, increase in bioavailable androgens via decreased sex hormone-binding globulin (SHBG) [ 38 ] ,and, potentially, modulation of LH secretion.
In 1992, Hales and Barker proposed the concept that the environmental influence of undernutrition in early life increased the risk of type 2 diabetes in adulthood [ 39 ] . They discovered a relationship between low birth weight and type 2 diabetes in men from England. In the “thrifty phenotype hypothesis,” malnutrition serves as a fetal and infant insult that results in a state of nutritional thrift. The adaptations result in postnatal metabolic changes that prepare the individual for survival under poor nutritional conditions. The adaptations become detrimental when the postnatal environment changes to one of an overabundance of nutrients, resulting in obesity and diabetes.
Insulin resistance is a component of the World Health Organization (WHO) de finition of the metabolic syndrome, which is a cluster of risk factors for cardiovascular disease [ 40 ] . The WHO defines the metabolic syndrome as the presence of glucose intolerance or insulin resistance, with at least two of the following: hypertension, dyslipidemia, obesity, and microalbuminuria. Women with PCOS are 4.4 times more likely to have the metabolic syndrome, so it becomes prudent to screen these patients, especially in those with insulin resistance [ 41 ] .
Lipid abnormalities are also more prevalent in PCOS patients. There can be a significant increase in total cholesterol, LDL cholesterol, and triglycerides, and a decrease in HDL cholesterol compared to weight-matched controls [ 42 ] . The dyslipidemia, impaired glucose intolerance, central obesity, hyperandrogenism, and hypertension seen in PCOS patients greatly increase the risk for cardiovascular disease. Based on this risk profile, women with PCOS have a sevenfold increased risk of myocardial infarction [ 43 ] .
Laboratory Evaluation
In addition to confirming elevations of androgens, the laboratory evaluation of PCOS should have the objective of excluding other causes of hyperandrogenic anovulation. Androgen-producing tumors of the ovary and adrenals must be excluded. The adrenal glands contribute 98 % of circulating DHEAS, while both the ovaries and adrenals contribute equal amounts of circulating testosterone and androstenedione. If total testosterone is greater than 200 ng/dL or DHEAS is greater than 7,000 ng/dL, MRI is warranted to identify the hormone-secreting lesion. Measuring 17 a (alpha)-hydroxyprogesterone will screen for 21-hydroxylase deficiency, the most common enzyme deficiency in nonclassical CAH. A 17-hydroxyprogesterone level of greater than 3 ng/mL is defined as elevated and should be followed by an ACTH stimulation test, using 250 mg of synthetic ACTH given intravenously following an overnight fast. A 1-h increase of 17 a (alpha)-hydroxyprogesterone of more than 10 ng/mL is indicative of an enzyme defect in 21-hydroxylase.
Cushing’s syndrome may masquerade as PCOS. Those who have additional signs of Cushing’s syndrome, such as a moon facies, buffalo hump, abdominal striae, easy bruising, and proximal myopathy, should undergo screening with a 24-h urinary-free cortisol. In the work-up for anovulation, exclusion of prolactinoma should be performed. It is not uncommon to detect mild elevations in prolactin levels in PCOS patients. Thyroid-stimulating hormone (TSH) should be evaluated. LH, FSH, and estradiol levels should be obtained to exclude hypothalamic amenorrhea or premature ovarian failure.
Diabetes Screen/Evaluation of Insulin Resistance
The 2003 Rotterdam PCOS consensus group recommends a 2-h oral glucose tolerance test (OGTT) for obese PCOS patients and nonobese PCOS patients with risk factors for insulin resistance, such as family history of diabetes [ 2 ] . Defining insulin resistance is difficult, because the concept is nebulous with no universally accepted diagnostic strategy. The WHO defines insulin resistance as the lowest quartile of measures of insulin sensitivity. Women with PCOS are at significantly increased risk for impaired glucose tolerance and type 2 diabetes compared to age-, weight-, and ethnicity matched controls [ 44 ] . If either the fasting glucose is 126 mg/ dL or more, or the 2-h level is 200 mg/dL or more, diabetes is detected and should be confirmed with a repeat test. Impaired fasting glucose is defined as a glucose level between 100 and 126 mg/dL. Impaired glucose tolerance is defined as a 2-h glucose level between 140 and 200 mg/dL. It is also reasonable to obtain a fasting lipid profile in women suspected of having risk factors for cardiovascular disease. HgbA1C has been recently advocated as an accurate screening tool in evaluation of insulin resistance and diabetes in women with PCOS [ 45 ] .
Treatment
There are many considerations when deciding on therapy for PCOS (Fig. 8.4 ). Identification of patient concerns is necessary when prioritizing goals and formulating a treatment plan. A combination of therapies may be warranted, and the practitioner should appropriately counsel the patient on the treatment expectations. Amelioration of long-term health risks should be emphasized, regardless of the primary complaints of the patient.
Weight Loss
Weight reduction should be a major component of any treatment plan for the overweight patient (BMI >25). Any sustained improvement in weight should involve diet and exercise, and consultation with a nutritionist may be helpful for those with difficulty achieving weight reduction. Obese PCOS patients who achieve weight loss will have an increase in SHBG, decrease in free testosterone, and improvement in fasting insulin levels [ 46 ] .
Oral Contraceptives
Combination oral contraceptives have been the mainstay of PCOS management for the patient not interested in conception. Contraceptives suppress pituitary LH and consequently reduce ovarian androgen secretion, increase SHBG, and reduce free testosterone, while regulating menses and reducing the risk of endometrial hyperplasia or malignancy. However, there may be mild attenuation of insulin sensitivity.
Korytkowski et al. have shown that short-term use of COCs in PCOS women results in a small decrease in insulin sensitivity and no change in the baseline elevation in triglyceride levels [ 47 ] . However, in normal women, COCs were shown to have an even more pronounced decline in insulin sensitivity, along with a significant elevation in triglyceride levels. The long term effects of COCs upon insulin sensitivity and lipoprotein profiles have not been well documented. PCOS women are at greater risk for the development of diabetes and cardiovascular disease; thus, further investigation into the safety of long-term hormonal therapy is needed.
Hair Removal
In women with significant hirsutism, removal of unwanted hair, especially on the face, chest, and abdomen, is often an important concern. Shaving, plucking, waxing, and depilatories are the most common approaches used for temporary removal. These approaches do not induce coarser or faster hair growth, but must be repeated at frequent intervals. Electrolysis is probably the most commonly used technique for permanent hair removal, wherein a fine needle is inserted into each hair follicle and an electrical current is applied. Hair follicles must be treated individually and several treatments may be needed to destroy the follicle. Usually, repeated treatments are required over a 12- to 18-month period. Possible side effects include pain, infection, hyper or hypopigmentation, and keloid formation in susceptible women. Laser hair removal techniques, and the related intense pulsed light devices, are other options for hair removal. These techniques work by emitting light at various wavelengths, energy output, and pulse widths that are selectively absorbed by darker structures. For this reason, laser hair removal works best for light-skinned people with dark hair. As with electrolysis, laser treatments for hair removal must be repeated.
Topical Eflornithine Hydrochloride
Eflornithine hydrochloride (Vaniqa, Bristol-Myers Squibb, New York, NY) is a prescription-only topical cream approved by the FDA for reducing and inhibiting the growth of unwanted facial hair. This drug works by irreversibly inhibiting ornithine decarboxylase, an enzyme that facilitates cell division in hair follicles. The cream is applied twice a day to areas of unwanted facial hair, and <1 % is absorbed systemically. It is designated by the FDA as a Pregnancy Category C drug.
Noticeable results are usually observed after 4–8 weeks of therapy. Application must be continued for as long as inhibition of hair growth is desired, although facial hair growth is reduced for up to 8 weeks after discontinuation.
Antiandrogens
Antiandrogens are commonly used as an adjunct to oral contraceptive therapy for treatment of hirsutism, but they have also been found to improve ovulation and restore regular menses. It is important to remember that all antiandrogens are teratogenic and pose a risk of feminizing a male fetus, and thus should be used along with an effective form of contraception.
Spironolactone is an aldosterone antagonist, and it is the most commonly used adjunctive agent in the treatment of hirsutism. It competes for testosterone binding sites on the pilosebaceous unit, inhibits 5 a (alpha)-reductase, and inhibits androgen production by interfering with cytochrome P450 [ 48 ] . The potassium-sparing effect warrants judicious use in the patient on potassium supplementation or preexisting hypertension.
Flutamide is a nonsteroidal antiandrogen that competes for the androgen receptor. Anovulatory PCOS patients treated with flutamide experienced resumption of ovulation with restoration of normal ovarian appearance with one dominant follicle [ 49 ] . This study also reported a reduction in plasma levels of LH, androstenedione, and testosterone. Liver toxicity is a rare but potentially serious side effect of flutamide.
Finasteride is a potent inhibitor of 5 a (alpha)-reductase used for the treatment of prostatic hyperplasia with promising results as a treatment for hirsutism. All antiandrogens should be used along with a form of contraception, because they are teratogenic and pose a risk of feminizing a male fetus.
Insulin-Sensitizing Agents
Insulin-sensitizing agents have been shown to improve endocrine and reproductive abnormalities in PCOS. Metformin is the most thoroughly investigated insulin-lowering agent used in PCOS. It is a biguanide that primarily works by suppressing hepatic gluconeogenesis and, to a lesser degree, increases peripheral insulin sensitivity [ 50 ] . Thiazolidinediones (TZDs) are peroxisome proliferator activating receptor (PPAR- g (gamma)) agonists that improve peripheral insulin sensitivity but do not appear to have an effect on hepatic glucose production [ 50 ] . This class of medications includes troglitazone, pioglitazone, and rosiglitazone.
Troglitazone is the oldest but was removed from the market in 2000 owing to hepatotoxicity. Rosiglitazone and pioglitazone are still available and appear to be safer. The role of insulin-sensitizing agents is still an area of active investigation.
Many studies have demonstrated the positive effects of metformin on the reproductive axis of PCOS patients, with one of the most comprehensive studies recently demonstrating a dramatic improvement after 6 months of treatment. Metformin administration to nonobese hyperandrogenic PCOS patients resulted in a reduction of (1) LH pulse amplitude; (2) androstenedione levels; (3) testosterone levels; (4) ovarian volume; and (5) Ferriman-Gallwey scores. Menstrual cyclicity was also improved in most patients [ 51 ] . The investigators did not determine if metformin increased the likelihood of ovulation or if FSH levels rose. Similarly, troglitazone-treated PCOS patients demonstrated improved ovulation, decreased hirsutism, decreased free testosterone, and increased SHBG [ 52 ] .
Insulin-sensitizing agents have a favorable effect on hyperandrogenism by reducing LH secretion, thereby removing the main stimulus for pathologic ovarian and adrenal androgen production. The reduction in insulin levels elevates hepatic SHBG production, decreasing free androgen levels. The concurrent improvement in hyperinsulinemia and hyperandrogenemia conferred by the use of insulin-sensitizing agents may ameliorate hirsutism.
The improvement in ovulation and menstrual cyclicity in patients treated with insulin-sensitizing agents suggests improved fertility. Indeed, spontaneous and clomid-induced ovulation rates in metformin-treated women with PCOS are increased [ 53 ] . Spontaneous ovulation occurred in 34 % of those treated with 500 mg of metformin 3 times daily compared to only 4 % in the placebo group. Clomid-induced ovulation occurred in 90 % of women who received metformin compared to 8 % who received placebo. For those who are clomiphene-resistant, significant improvements in ovulation and pregnancy rates were reported in a randomized, double-blind, placebo-controlled trial for women pretreated with metformin [ 54 ] . Troglitazone alone and the combination of troglitazone plus clomiphene is also associated with increased rates (gamma) of ovulation and pregnancy in insulin-resistant women with PCOS [ 55 ] .
Though metformin is a category B medication, its use throughout pregnancy is becoming more attractive. In one retrospective study, Jakubowicz et al. found a significant reduction in the rate of early pregnancy loss for PCOS women who conceived while taking metformin and continued the agent throughout pregnancy. The rate of early pregnancy loss in the metformin group was 8.8 % compared to 41.9 % in controls. In the women with a prior history of miscarriage, the early loss rate was 11.1 % for the metformin group compared with 58.3 % in the control group [ 56 ] . The efficacy of metformin for pregnancy loss is not yet clear, and safety data for this indication are lacking. In 2007, Legro et al. published a well-designed trial that concluded that live birth rate in PCOS patients prescribed clomiphene (22.5 %) was superior to metformin alone (7.2 %) and not dissimilar from combination clomiphene/metformin therapy (26.8 %) [ 57 ] .
Metformin should not be given to those with conditions associated with elevated lactate levels, such as renal or hepatic disease, as there is a risk of lactic acidosis with an associated mortality of 50 % [ 58 ] . Although most studies of metformin in PCOS used a dose of 500 mg 3 times daily, no studies have been performed to determine the optimal dosing regimen for improvement in insulin sensitivity, reduction of androgens, and resumption of ovulation. A dose–response study of type II diabetic patients demonstrated that the 2,000-mg daily dose was optimal for improvement of glucose homeostasis [ 59 ], but the relevance of this dose to the PCOS population remains to be investigated.
Metformin should be initiated in a stepwise approach, titrating the dose slowly over several weeks in order to minimize side effects. Most patients will experience gastrointestinal symptoms such as nausea, diarrhea, indigestion, and abdominal discomfort. Side effects will resolve in several days for most patients, which allows incremental dosing increases on a weekly basis up to a maximum dose of 1,000 mg bid. Baseline serum creatinine should be obtained with yearly monitoring to avoid lactic acidosis.
There are no guidelines currently on the long-term use of metformin to prevent or improve health outcomes in patients with PCOS. One of the serious reactions of TZD is hepatotoxicity. Initiation of treatment requires baseline liver function studies along with periodic monitoring.
Ovarian Surgery
Ovarian Wedge Resection
Ovarian wedge resection is a surgical procedure used for PCOS patients that has been found to restore both regular menses and ovulation in the majority of cases. This procedure, originally performed by laparotomy, consisted of removing a wedge of ovarian tissue and reconstructing the ovary. Laparoscopic techniques for ovarian wedge resection have described.
The primary disadvantage of this approach is the formation of significant pelvic adhesions, which occurs in at least one third of the patients. The concern is that these adhesions might actually decrease fertility and increase the risk of pelvic pain. Another concern is that the restoration of ovulation is unlikely to be permanent, since the ovaries are not the causal agents in this complex systemic disorder. However, the actual long-term effectiveness of wedge resection has never been reported.
Ovarian Drilling
A laparoscopic variant with similar results to ovarian wedge resection is called ovarian drilling. This procedure involves making multiple punctures in the ovarian cortex and destroying ovarian tissue using unipolar electrosurgery or laser. The results and complications for this approach appear to be similar or slightly less than those for ovarian wedge resection, although a prospective randomized study has never been done. There are additional concerns about long-term effects of ovarian drilling on ovarian function.
References
1. Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. Polycystic ovary syndrome. Boston: Blackwell Scienti fic; 1992. p. 377–84.
2. The 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.
3. Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries—a common finding in normal women. Lancet. 1988;1(8590):870–2.
4. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeast United States: a prospective study. J Clin Endocrinol Metab. 1998;83(9):3078–82.
5. O’Driscoll J, Mamtora H, Higginson J, Pollock A, Kane J, Anderson D. A prospective study of the prevalence of clear-cut endocrine disorders and polycystic ovaries in 350 patients presenting with hirsutism or androgenic alopecia. Clin Endocrinol. 1994;41:231–6.
6. Hatch R, Rosen fi eld R, Kim M, Tredway D. Hirsutism: implications, etiology, and management. Am J Obstet Gynecol. 1981;140: 815–30.
7. Betti R, Bencini P, Lodi A, Urbani C, Chirelli G, Crosti C. Incidence of polycystic ovaries in patients with late-onset or persistent acne: hormonal reports. Dermatologica. 1990;181:109–11.
8. Cela E, Robertson C, Rush K, Kousta E, White DM, Wilson H, et al. Prevalence of polycystic ovaries in women with androgenic alopecia. Eur J Endocrinol. 2003;149:439–42.
9. Carmina E, Lobo R. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with signi fi cant morbidity in women. J Clin Endocrinol Metab. 1999;84(6):1897–9.
10. Dunaif A, Graf M. Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest. 1989;83:23–9.
11. Arner P. Control of lipolysis and its relevance to development of obesity in man. Diabetes Metab Rev. 1988;4:507–15.
12. Barbieri R, Ryan K. Hyperandrogenism, insulin resistance and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol. 1983;147: 90–101.
13. Sagle M, Bishop K, Ridley N. Recurrent early miscarriage and polycystic ovaries. BMJ. 1988;297:1027–8.
14. Gray R, Wu L. Subfertility and risk of spontaneous abortion. Am J Public Health. 2000;90(9):1452–4.
15. Regan L, Braude P, Trembath P. Influence of past reproductive performance on risk of spontaneous abortion. BMJ. 1989;299:541–5.
16. Liddell H, Sowden K, Farquhar CM. Recurrent miscarriage: screening for polycystic ovaries and subsequent pregnancy outcome. Aust N Z J Obstet Gynaecol. 1997;37(4):402–6.
17. Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod. 1994;9(7):1328–32.
18. Homburg R, Armar N, Eshel A, Adams J, Jacobs H. In fl uence of serum luteinising hormone concentrations on ovulation conception, and early pregnancy loss in polycystic ovary syndrome. BMJ. 1988;297(1024):1026.
19. Yen SS, Vela P, Rankin J. Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovary disease. J Clin Endocrinol Metab. 1970;30:435–42.
20. Berga S, Guzick D, Winters S. Increased luteinizing hormone and a-subunit secretion in women with hyperandrogenic anovulation. J Clin Endocrinol Metab. 1993;77(4):895–901.
21. Morales A, Laughlin GA, Butzow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab. 1996;81:2854–64.
22. Hayes F, Taylor A, Martin K, Hall J. Use of a gonadotropin-releasing hormone antagonist as a physiologic probe in polycystic ovary syndrome: assessment of neuroendocrine and androgen dynamics. J Clin Endocrinol Metab. 1998;83(7):2343–9.
23. Knobil E. Neuroendocrine control of the menstrual cycle. Recent Prog Horm Res. 1980;36:53.
24. Rasmussen DD, Gambacciani M, Swartz W, Tueros VS, Yen SS. Pulsatile gonadotropin-releasing hormone release from the human medibasal hypothalamus in vitro: opiate receptor-mediated suppression. Neuroendocrinology. 1989;49:150.
25. Prevot V, Croix D, Bouret S, Dutoit S, Tramu G, Stefano GB, et al. De fi nitive evidence for the existence of morphological plasticity in the external zone of the median eminence during the rat estrous cycle: implication of neuro-glio-endothelial interactions in gonadotropin- releasing hormone release. Neuroscience. 1999;94:809–19.
26. Daniels T, Berga S. Resistance of gonadotropin releasing hormone drive to sex steroid-induced suppression in hyperandrogenic anovulation. J Clin Endocrinol Metab. 1997;82(12):4179–83.
27. Kalro BN, Loucks TL, Berga SL. Neuromodulation in polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2003;14:529–55.
28. Kamberi IA, Mical RS, Porter JC. Hypophysial portal vessel infusion: in vivo demonstration of LRF, FRF, and PIF in pituitary stalk plasma. Endocrinology. 1971;89:1042–6.
29. Findell PR, Wong KH, Jackman JK, Daniels DV. B1-Adrenergic and dopamine (D1)-receptors coupled to adenylyl cyclase activation in GT1 gonadotropin-releasing hormone neurosecretory cells. Endocrinology. 1993;132(2):682–8.
30. Pons S, Torres-Aleman I. Estradiol modulates insulin-like growth factor I receptors and binding proteins in neurons from the hypothalamus. J Neuroendocrinol. 1993;5:267–71.
31. de Ziegler D, Steingold K, Cedars M, Lu JK, Meldrum DR, Judd HL, et al. Recovery of hormone secretion after chronic gonadotropinreleasing hormone agonist administration in women with polycystic ovarian disease. J Clin Endocrinol Metab. 1989;68(6):1111–7.
32. Velazquez E, Mendoza S, Hamer T, Sosa F, Glueck C. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994;43(5):647–54.
33. Chang RJ, Mandel FP, Wolfsen AR, Judd HL. Circulating levels of plasma adrenocorticotropin in polycystic ovary disease. J Clin Endocrinol Metab. 1982;54(6):1265–7.
34. Mason HD, Willis DS, Beard RW, Winston RM, Margara R, Franks S. Estradiol production by granulosa cells of normal and polycystic ovaries: relationship to menstrual cycle history and concentrations of gonadotropins and sex steroids in follicular fl uid. J Clin Endocrinol Metab. 1994;79(5):1355–60.
35. Cof fl er MS, Patel K, Dahan MH, Malcom PJ, Kawashima T, Deutsch R, et al. Evidence for abnormal granulosa cell responsiveness to follicle-stimulating hormone in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(4):1742–7.
36. Ovalle F, Azziz R. Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus. Fertil Steril. 2002;77(6):1095–105.
37. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18:774–800.
38. Nestler J, Powers L, Matt D, Steingold KA, Plymate SR, Rittmaster RS, 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;72:83–9.
39. Hales C, Barker D. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35: 595–601.
40. World Health Organization (WHO). Definition, diagnosis and classi fi cation of diabetes mellitus and its complications. Report of a WHO Consultation, part 1: diagnosis and classification of diabetes mellitus. Geneva: WHO; 1999.
41. Talbott E, Zborowski J, Rager J, Boudreaux M, Edmundowicz D, Guzick D. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calci fi cation among women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89(11):5454–61.
42. Wild RA, Painter PC, Coulson PB, Carruth KB, Ranney GB. Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1985;61:946–51.
43. Dahlgren E, Janson PO, Johansson S, Lapidus L, Oden A. Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet Gynecol Scand. 1992;71(8):599–604.
44. Legro R, Kunselman A, Dodson W, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84(1): 165–9.
45. Hurd WW, Abdel-Rahman MY, Ismail SA, Abdellah MA, Schmotzer CL, Sood A. Comparison of diabetes mellitus and insulin resistance screening methods for women with polycystic ovary syndrome. Fertil Steril. 2011;96(4):1043–7.
46. Guzick D, Wing R, Smith D, Berga S, Winters S. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril. 1994;61(4):598–604.
47. Korytkowski M, Mokan M, Horwitz M, Berga S. Metabolic effects of oral contraceptives in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1995;80(11):3327–34.
48. Cumming D, Yang J, Rebar R, Yen S. Treatment of hirsutism with spironolactone. JAMA. 1982;247(9):1295–8.
49. De Leo V, Lanzetta D, D’Antona D, la Marca A, Morgante G. Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83(1):99–102.
50. Inzucchi S, Maggs D, Spollett G, Page SL, Rife FS, Walton V, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med. 1998;338(13):867–72.
51. Genazzani A, Battaglia C, Malavasi B, Strucchi C, Tortolani F, Gamba O. Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertil Steril. 2004;81(1):114–9.
52. Azziz R, Ehrmann D, Legro R, Whitcomb RW, Hanley R, Fereshetian AG, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebocontrolled trial. J Clin Endocrinol Metab. 2001;86(4):1626–32.
53. Nestler J, Daniela J, Evans W, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338:1876–80.
54. Vandermolen D, Ratts V, Evans W, Stovall D, Kauma S, Nestler J. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75:310–5.
55. Mitwally M, Kuscu N, Yalcinkaya T. High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome. Hum Reprod. 1999;14:2700–3.
56. Jakubowicz D, Iuorno M, Jakubowicz S, Roberts K, Nestler J. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(2):524–9.
57. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–6.
58. De Leo V, la Marca A, Petraglia F. Insulin-lowering agents in the management of polycystic ovary syndrome. Endocr Rev. 2003;24(5):633–67.
59. Garber A, Duncan T, Goodman A, Mills D, Rohlf J. Efficacy of metformin in type II diabetes: results of a double-blind, placebocontrolled, dose–response trial. Am J Med. 1997;103:491–7.