Download PCOS Treatment option 2008 Treatment for Polycystic Ovary

PCOS Treatment option 2008
Treatment for Polycystic Ovary Syndrome: A Critical Appraisal of
Treatment Options
Shahla Nader
Expert Rev Endocrinol Metab. 2008;3(3):349-359. ©2008 Future Drugs Ltd.
Posted 07/10/2008
Abstract
The management of polycystic ovary syndrome (PCOS) usually spans a woman's reproductive years. While the treatment of symptoms is a primary concern, given its long-term
nature, the benefits and potential risks need to be assessed and balanced. The variability of presentation coupled with the phenotypic diversity of this patient population,
requires the individualization of treatment to each patient. Periodically, the regimen has to be modified owing to a desire for pregnancy, necessitating ovulation induction in this
anovulatory group of women. Finally, for any treatment offered, consideration should be given to potential adverse effects on the fetus should spontaneous ovulation and
unplanned pregnancy occur. This review highlights the current issues surrounding PCOS and provides a critical appraisal of treatment options.
Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting approximately 6% of this population.[1] The clinical issues in
PCOS relate to menstrual irregularities, symptoms of excess androgen and cystic ovaries. [2] While not universal, and not part of the definition, insulin resistance and obesity are
also extremely common accompaniments of this syndrome. [2,3] This phenotypic nonuniformity and the variability of presentation have made it difficult to define the syndrome.
The 1990 NIH-sponsored conference definition required oligo-ovulation, clinical or biochemical hyperandrogenism and the exclusion of other known disorders, such as lateonset congenital adrenal hyperplasia and Cushing's syndrome. The more recent 2003 Rotterdam consensus workshop was in response to an increasing awareness that the
clinical expression of PCOS may be broader.[4] It defined PCOS as a syndrome encompassing two out of three criteria, namely oligo-ovulation, clinical and/or biochemical signs
of hyperandrogenism and polycystic ovaries, after the exclusion of other entities. While this has been a practical working definition, others believe that hyperandrogenism should
be an integral part of the definition.[5] This brief overview outlines the management options for women with PCOS. Given the limited clinical goals, it should be straightforward
but, clearly, it is not. The phenotypic diversity, differences in underlying pathogenesis and the secondary effects of medications administerd to ameliorate symptoms, such as
those of hyperandrogenism, and outcomes, such as anovulatory infertility, make treatment decisions for the practicing physician quite difficult. The complexity of these effects
and decisions forms the basis of this review.
Treatment of Androgen-related Symptoms
The over-riding androgenic symptoms that the individual presents will vary from patient to patient: for some, it is mainly hirsutism but for others it is acne and/or alopecia. Many
have both hirsutism and acne and a few complain of significant acne, hirsutism and alopecia. Those with acne have often used topical treatment and oral medications, such as
antibiotics and isotretinoin, and have relapsed.
Hirsutism
Overall, 70-80% of women with excess androgen demonstrate hirsutism, [6] usually defined as a Ferriman-Gallway score of at least 8, although this prevalence is less in certain
ethnic groups, such as East Asians, who may have fewer hair follicles endowed per unit area of skin. Androgens increase the growth rate of hair and transform vellus hair to
terminal hair. Reduction of androgens reduces new hair growth and slows the growth of terminal hair already present. [7,8] Hair grows in nonsynchronous cycles. The growth or
anagen phase varies according to body area and is approximately 4 months for facial hair. Given this long hair growth cycle, the effects of hormonal therapy require more than 6
months to be maximal.
Oral Contraceptive Pills. Oral contraceptive pills (OCPs) contain varying doses of ethinylestradiol and varying doses and formulations of progestins. The androgen-lowering
effect of OCPs relate to the progestin-induced reduction of luteinizing hormone (LH), which stimulates ovarian androgen secretion, and the estrogen-mediated increase in sex
hormone-binding globulin (SHBG). Increased SHBG binds testosterone. This dual effect (decreased secretion and increased binding of androgens) lowers free, biologically
active androgens, hence the beneficial effects of OCPs on hirsutism.[9-11] The higher the estrogen content the greater the effect on SHBG. Available low-dose OCPs (defined as
<50 µg) contain ethinylestradiol in doses ranging from 15 to 35 µg in Europe and 20 to 35 µg in the USA. Some biphasic and triphasic formulations contain up to a 40-µg dose
for a few days of the cycle.[11] In addition, an important consideration for the progestin component is the degree of androgenicity of the progestin. [11] Newer OCPs contain less
androgenic progestins (such as desogestrel and norgestimate) and two progestins: cyproterone acetate (CPA), used in low doses in OCPs, and drospirenone, function as
androgen receptor antagonists, CPA being more potent in its effect. CPA may also inhibit 5-α-reductase activity, decreasing the availability of the more potent androgen,
dihydrotestosterone.[12] Unfortunately, CPA-containing OCPs are not available in the USA. A third anti-androgenic progestin, dienogest, has recently become available in Europe
and combined with estradiol as an OCP.
Anti-androgens. Spironolactone, which is an aldosterone antagonist, is a dose-dependent competitive inhibitor of the androgen receptor and can also inhibit 5-α-reductase
activity.[13] It has demonstrable effects on hirsutism over and above those induced by OCPs.[14] While generally well tolerated, it occasionally causes fatigue, postural
hypotension and dizziness and, administered alone in high doses, may cause menstrual irregularity. The risk of feminizing a male fetus, if pregnancy occurs, precludes its use
as monotherapy in sexually active women with PCOS. Thus, it is often used with OCPs.
Cyproterone acetate is a progestogenic compound with anti-androgenic activity. Used in high doses (50-100 mg) and in reverse sequential regimen (for the first 10 days of
cycle), in combination with ethinylestradiol 20-50 µg (to ensure regular menses), it was shown to be more effective than finasteride, a 5-α-reductase inhibitor.[15] CPA is
generally well tolerated, although it may cause headaches, nausea, weight gain, breast tenderness, loss of libido and, rarely, hepatotoxicity effects. As with spironolactone,
there is a risk of feminizing a male fetus. CPA by itself is also not available in the USA.
Flutamide is a nonsteroidal, selective, anti-androgen without progestogenic effect. In a dose of 500 mg daily, it was found to be similarly effective as spironolactone 100 mg [16] in
women with idiopathic hirsutism and, in a recent study, the minimal effective dose was found to be 125 mg daily. [17] Its major concern is serious hepatotoxicity, although doses
up to 375 mg have been used without any significant hepatotoxicity. [17,18]
Finasteride inhibits type 2 5-α-reductase.[19] However, enhanced 5-α-reductase activity in hirsutism probably involves both type 1 and 2 enzymes. Hirsutism scores were lowered
in studies of finasteride.[20,21] Comparison of finasteride with spironolactone has shown equal [21] or lesser efficacy of finasteride.[22] Finasteride has also been used in
combination with a CPA-containing OCP, and the addition of finasteride 5 mg to the OCP was shown to be better than the OCP alone. [23] When finasteride was compared
directly with an OCP containing low-dose CPA, the effect was equivalent.[24] While finasteride has a low side-effect profile, its feminizing effects on a male fetus preclude its use
in most patients.
Glucocorticoids. Glucocorticoids suppress adrenal androgen secretion and have been used in patients with adrenal hyperandrogenism. Their use i s most legitimate in patients
with classic congenital adrenal hyperplasia, where they can help prevent and manage hirsutism and allow ovulatory cycles. In nonclassic congenital adrenal hyperplasia, and in
functional adrenal androgen excess (a minority of PCOS patients), their role is more limited. [25] Suppression of adrenal androgens results in a minor improvement of hirsutism,
although prolonged remission after therapy withdrawal can be obtained. [26] A trial of CPA versus hydrocortisone in patients with late-onset congenital adrenal hyperplasia
showed a greater decrease in hirsutism scores with 1 year of CPA compared with hydrocortisone (54 vs 26%). These results occurred despite a greater reduction of androgens
with glucocorticoids, highlighting the importance of peripheral receptivity to androgens. [27] Overdosing can occur, leading to adrenal atrophy, weight gain and decreased bone
mineral density.
Gonadotropin-releasing Hormone Agonists. Since lowering of LH reduces ovarian androgen secretion, benefits would be expected from gonadotropin-releasing hormone
(GnRH) agonist use. However GnRH agonists cannot be used long-term alone because the hypoestrogenic state induced is detrimental to bone health. Administered with
estrogen-progestin add-back, they were shown to be more effective for hirsutism than an OCP in two trials.[28,29] Their expense, parenteral administration and side effects
essentially preclude their use, except for patients who are severely hirsute, such as those with hyperthecosis.
Insulin-lowering Agents. Both metformin and thiazolidinediones may lower ovarian androgen secretion, mainly through their insulin-lowering effects.[30] In a Cochrane Databse
Systematic Review article, limited data in a small numbers of patients have shown no evidence of a difference in effect between metformin and OCPs on hirsutism and acne.[31]
Some effects of rosiglitazone on hirsutism was shown by Yilmaz et al.,[30] and troglitazone (no longer available) improved hirsutism in women with PCOS. [32]
Direct Hair Removal. Electrolysis has been is use for many years to remove unwanted hair. A fine needle is inserted into the hair follicle and an electrical current is applied.
Erythema and postinflammatory pigment changes may occur and scarring is possible. [33] Photoepilation uses laser and nonlaser light sources to damage hair follicles but vellus
hair remains and can be converted to terminal hair. While laser treatment is more expensive, it is less painful and much faster.[34] There is potential for depigmentation and
scarring with laser use, especially in darker-skinned women.
Topical Treatment. Eflornithine is an inhibitor of ornithine decarboxylase, an enzyme necessary for hair growth. A topical preparation of this inhibitor is available for unwanted
facial hair, taking 6-8 weeks for its effect to be apparent.[35] It can be combined with laser treatment.
Combination Therapy. In the Endocrine Society Practice Guidelines discussing the evaluation and treatment of hirsutism in premenopausal women, it was recommended that
oral contraceptives or direct hair removal be used initially. Then, if at least 6 months of OCP therapy has not significantly decreased the rate of hair growth, anti-androgens may
be added.[36]
Acne
Both OCPs and anti-androgens have been used successfully in the treatment of acne. [37] Within 3-6 months of OCP treatment, inflammatory acne counts are reduced by 3060%, with improvement in 50-90% of patients.[38] OCPs are especially useful in patients with deep-seated nodules and helpful in patients relapsing on isotretinoin.
Alopecia
There are no extensive trials for alopecia but OCPs and androgen blockers are usually administered and, in limited studies, CPA has had some effect, as has finasteride.[39]
Critical Appraisal of the Outcome & the Risks/Benefits of the Long-term
Treatment of PCOS
As stated previously, insulin resistance is commonly, though not universally, found in PCOS, [40] with prevalence being estimated in 50-70% of cases. Obesity, seen in
approximately 60% of cases, amplifies the severity of PCOS presentation. [41] The prevalence of obesity varies according to geographic location: it is greater in the USA than in
other places.[42] Of obese women with PCOS, 10% have undiagnosed diabetes and 35% have impaired glucose tolerance. [43] Almost 70% of patients with PCOS have an
abnormal lipid profile[44] and high triglycerides and low high-density lipoprotein (HDL) cholesterol are often found. The prevalence of metabolic syndrome in women with PCOS is
approximately 43-46%[45] and several studies using intima media thickness as a surrogate for cardiovascular risk evaluation have shown potential increased cardiovascular risk
in women with PCOS.[46-48] A similar study using coronary artery calcification as risk stratification has shown increased risk in patients with PCOS. [49]
While the findings mentioned are reflective of patient populations in the respective studies, it is worth pointing out again that there is considerable phenotypic variability in PCOS
and an individual patient with PCOS may not be at risk of any adverse effect. [40] Thus, while we can broadly discuss risks, the critical appraisal of potential long-term
benefits/risks of any treatment will have to be determined individually, as best as it is possible to be determined. Understanding and addressing the heterogeneity of PCOS is
fundamental to its approach.
One of the most commonly used medications in PCOS patients are OCPs. In addition to their androgen-lowering effects, it is likely that they protect the endometrium against
hyperplasia and cancer (as they do in the general population) and may also reduce the incidence of functional follicular ovarian cysts, as shown in the general population. One
of the earliest prospective studies of carbohydrate metabolism in women on OCPs in the general population, was that of Wynn and Doar.[50] Using high-dose OCPs, they found
that both oral and intravenous glucose tolerance AUC deteriorated in 78 and 70% of women, respectively, and 13% developed chemical diabetes. Significant elevations of
plasma insulin also occurred. The authors wrote 'the most important question of all, namely whether impairment of glucose tolerance and increased plasma insulin levels will
accelerate the rate of development of clinical diabetes and also of atherosclerosis requires careful consideration'. While high-dose OCPs are now seldom used, it is pertinent to
note that a meta-analysis of the association of low-dose OCPs with cardiovascular arterial disease found an increased risk of myocardial infarction and strokes with low-dose
pills, with an odds ratio of 2.01, including an increased risk of ischemic stroke with third-generation OCPs.[51]
Using lower dose OCPs, two euglycemic clamp studies showed there was no change to insulin sensitivity [52] when using a CPA-containing OCP, and a reduced sensitivity when
using an OCP containing either desogestrel or gestodene.[53] In a comprehensive review entitled 'The Influence of Female Sex Steroids on Glucose Metabolism and Insulin
Action.',[54] Godsland summarized the literature as showing that OCPs were generally associated with reduced glucose tolerance, hyperinsulinemia and insulin resistance; the
estrogen component was felt to be primarily responsible and progestins could modify these effects. In addition, the more androgenic progestins could also induce insulin
resistance directly.
A review of the literature on the metabolic impact of OCPs in PCOS revealed conflicting data: some studies showed improvement, others no change and some studies showed
deterioration, even to frank diabetes. It was hypothesized that the phenotypic and genetic variability of the PCOS population studied could impact the outcome, at least
regarding carbohydrate metabolism.[11] For example, lean PCOS patients could see an improvement in carbohydrate metabolism on OCPs, [55] which was possibly related to a
reduction of free androgens (as could those who lost weight),[56] while obese patients who were also genetically insulin resistant were likely to see deterioration, [57] or become
frankly diabetic.[58] Stratification of patients, encouragement of weight loss and exercise and other strategies of risk reduction are, thus, paramount in the treatment of the obese,
insulin-resistant PCOS patient. While the long-term benefits have not been extensively documented, use of insulin-lowering and -sensitizing medications, such as metformin,
would be advisable, although they are unapproved for such use in the USA. A recent, uncontrolled, retrospective, observational study, showing that long-term treatment with
metformin delays or prevents the development of impaired glucose tolerance and diabetes in women with PCOS, is certainly in keeping with this concept, [59] as is another study
showing decreased weight and systolic blood pressure and increased HDL in metformin-treated women with PCOS.[60] In this study, metformin was also shown to increase
insulin sensitivity and lower testosterone in obese but not nonobese PCOS women.
While similar arguments could, potentially, be made for the use of thiazolidinediones, the weight gain associated with their use may be unacceptable to the young female
population. In addition, questions regarding long-term cardiovascular safety in relation to their use in diabetic patients have been raised. [61] Nonetheless, their ability to prevent
or delay diabetes may potentially override such considerations, and their use was discussed recently in a position statement from the Androgen Excess Society. [62] In a proof-ofconcept study in young women, the addition of pioglitazone to flutamide and metformin, plus an estrogen and progestin preparation, led to improvements in endocrine-metabolic
parameters, decreasing inflammation and visceral fat and improving markers of cardiovascular health. [63] Further studies of their risks/benefits are clearly needed.
Anti-androgens, such as CPA, spironolactone and the 5-α-reductase inhibitor, finasteride, are generally well tolerated. As yet, no major long-term risk has been associated with
their use. All are expected to cause feminization of a male fetus and are, thus, contraindicated in sexually active PCOS patients without the concomitant use of effective
contraception. Thus, the decision to prescribe OCPs is often determined by the patient's circumstances, such as the use of other medications, rather than the specific
risks/benefits of OCPs. Flutamide's potential for hepatotoxicity essentially limits its major use, however, it has been shown to modify risk factors favorably. [64]
Except in the context of congenital adrenal hyperplasia, glucocorticoids' benefit on acne and hirsutism is limited and the potential for overtreatment with resultant weight gain,
bone loss and impairment of insulin sensitivity is significant and long-term use is discouraged. Their short-term use in ovulation induction may be more acceptable.
Risk modification and symptom relief (e.g., restoration of ovulatory cycles) has clearly been achieved with life-style modification and weight loss.[65] All strategies for weight loss,
including surgery, need to be explored in PCOS patients. For example, the combination of weight-reducing medications and group lifestyle modification was shown to be more
effective than either alone, in a group of obese adults. [66] Bariatric surgery as treatment for obesity is highly relevant to the PCOS population, and has been shown to reverse
much of the metabolic, as well as the reproductive, problems in these patients, including hirsutism.[67,68] In a study of morbidly obese PCOS women, weight loss was paralleled
by a decrease in hirsutism score, testosterone and dehydroepiandrosterone sulfate; amelioration of insulin resistance occurred and ovulatory cycles were also restored.[67] In
addition to these benefits, bariatric surgery for severe obesity has been associated with a decreased overall mortality. [69]
In the author's view and with critical appraisal of the available literature, whether insulin-lowering agents, in particular metformin, are helpful in hirsutism and acne is not so
important. What is important is that these agents may possibly negate and reduce adverse metabolic effects for the patient, particularly if medications, such as OCPs, which
may worsen these effects in a given patient, are used. In the occasional overweight or obese anovulatory patient, whose androgenic symptoms are mild, restoration of regular
cycles and ovulation by metformin alone is highly desirable, obviating the need for other agents, so long as contraception is not required.
In a crossover trial, statins were shown to decrease androgens over and above values induced by OCPs, improve hirsutism, decrease LH and low-density lipoprotein
cholesterol, and decrease C-reactive protein and other markers of endothelial activation; they also prevented the hypertriglyceridemia induced by OCPs. [70] Thus, statins may
negate some of the adverse metabolic effects of PCOS and its treatment with OCPs. However, in this study, [70] decreased insulin sensitivity and increased glucose and insulin
AUCs, commonly seen with OCPs, was unaffected by the use of statins.
PCOS in Adolescents
While PCOS is a continuum, its presentation is often during the adolescent years. The management at this time deserves special consideration and several authors have
addressed issues pertaining to this group. Arslanian et al. have shown the benefit of metformin, not only in improving metabolic parameters, but also in ameliorating functional
adrenal hyperandrogenism.[71] Glueck et al. showed that in overweight and obese adolescents, metformin plus a change of diet reduced weight, insulin resistance, total
cholesterol and triglycerides, and facilitated the resumption of regular menses. [72] Mastorakis et al. evaluated the effects of two different oral contraceptives on lipid profiles on
adolescents.[73] Higher triglycerides levels were seen, especially with the use of the less androgenic pills. The impact of this on long-term cardiovascular risk in this group of
patients who already have higher triglycerides is unknown and deserves further study. HDL cholesterol generally increases with OCP use in PCOS, unless the pill is significantly
androgenic. In a review concerning adolescents, Ibanez and de Zegher explained that while OCPs treat symptoms such as acne and menstrual irregularities, the 'upstream'
pathophysiologic cascade, such as hyperinsulinemia, may remain unaltered or may even worsen. [74] They pointed out that flutamide-metformin counter the 'upstream'
anomalies, such as hyperinsulinemia and hyperandrogenism, preventing or reversing 'downstream' effects. Owing to the potential for embryotoxicity, flutamide cannot be used
in sexually active adolescents and under such circumstances an OCP should be added. In a subsequent report by the authors, the proof-of-concept study quoted previously,
pioglitazone added to flutamide, metformin and an OCP, improved markers of cardiovascular health in young women. [63]
Ovulation Induction in PCOS
In PCOS, anovulation relates to low follicle-stimulating hormone (FSH) concentrations and the arrest of antral follicle growth in the final stages of maturation. [75,76] Excess LH,
androgens and insulin may individually or collectively play a direct or indirect role in this process, augmenting steroidogenesis but arresting follicular growth. For many women,
anovulatory infertility is the presenting complaint. Medications and other options available for the induction of ovulation are reviewed in the following sections.
Clomiphene Citrate. Clomiphene citrate is an estrogen receptor antagonist that interferes with negative feedback of the estrogen-signaling pathway, resulting in increased
availability of FSH. Increased FSH leads to follicular growth, followed by the LH surge and ovulation. Doses of 50-150 mg are administered for 5 days, starting on days 3 or 5 of
a progestin-induced or spontaneous cycle. Ovulation occurs in 70-80% of treated patients with a cumulative live-birth rate of 41%.[77,78]
Pure FSH. Pure FSH is approved for use in patients with clomiphene resistance and failure; it does not have estrogen antagonistic effects. Used daily, subcutaneously
administered FSH injections induce follicular growth, estradiol production and result in the development of one or more mature Graafian follicles. Human chorionic gonadotropin
is used as a surrogate for the LH surge, leading to maturation of the oocyte, rupture of the follicle and formation of the corpus luteum. Treatment with FSH is expensive, time
consuming and requires expertise and stringent monitoring. The therapeutic dose range is narrow, PCOS patients are high responders and the minimum threshold can easily be
exceeded, leading to multiple gestation caused by the growth and development of multiple mature follicles. [79] Less commonly, severe ovarian hyperstimulation can occur. This
life-threatening complication is related to human chorionic gonadotropin-mediated production of vasoactive mediators after gonadotropin induced multifollicular development. [80]
Either or both of these complications can occur in any given cycle. For this reason, a step-up dose-finding approach favoring unifollicular development is recommended.
Insulin-lowering Agents. Insulin resistance, exacerbated by obesity, is commonly found in PCOS patients. Hyperinsulinemia contributes to anovulation by increasing ovarian
androgen synthesis. Many of the obese, insulin-resistant patients are also clomiphene resistant. Insulin-lowering agents, such as metformin and thiazolidinediones, can reduce
androgen concentrations with a potential for inducing ovulation.
Metformin used off-label has been investigated in several studies. A Cochrane Database Systematic Review article of clinical trials comparing metformin with placebo for
ovulation induction in PCOS found metformin to be more effective than placebo in inducing ovulation with an odds ratio of 3.9 (confidence interval: 2.3-6.7) and its choice as a
first-line agent was felt to be appropriate.[81] The relative efficacy of clomiphene versus metformin has been investigated in two recent randomized trials, one prospective
nonrandomized trial and also in one observational study, with divergent and contradictory outcomes. In an unselected group of 228 anovulatory women with PCOS, randomized
to treatment groups, metformin plus clomiphene was no more beneficial than clomiphene plus placebo in inducing ovulation, achieving ongoing pregnancy or in miscarriage
rates.[82] Palomba et al. evaluated clomiphene versus metformin as first-line treatment in two trials,[83,84] one randomized[83] and, in the other, the patients were matched
according to age and BMI:[84] while the earlier trial showed advantages of metformin over clomiphene, their more recent trial showed equal efficacy regarding ovulation,
pregnancy and miscarriage rates. They attributed these differences to the fact that the earlier trial had selectively studied nonobese patients while their second trial was more
representative of the overall PCOS population. In a retrospective, observational comparative study by Neveu et al., patients were initially administered either clomiphene citrate
or metformin, based on patient preference and profiles. [85] The authors demonstrated that metformin was better than clomiphene as first-line treatment for ovulation induction;[85]
pregnancy rates were equivalent. Patients who conceived did so within the first 6 months of taking clomiphene, while some patients on metformin required over 1 year of
treatment to conceive. Finally, in a large head-to-head randomized trial comparing clomiphene with metformin, [86] there were significantly more live births following clomiphene
treatment than with metformin (23 vs 7%). While the ovulation rate was also higher in the clomiphene group versus the metformin group, it was highest in patients who took both
agents.
The BMIs of the patients in these various trials were very different. In the Moll trial of clomiphene versus clomiphene plus metformin,[82] while the mean BMIs were 27.8 and
28.5, respectively, the BMI was 25 or lower in almost half of the subjects. In the earlier, nonobese, Palomba trial it did not exceed 30, with a mean of 27 and 26.7 for metformin
and clomiphene, respectively,[83] whereas in their second, more inclusive, trial it ranged from 15.8 to 34.1 [84] with a median of 26.7 for metformin and 26.5 for clomiphene; 39.7%
of the subjects were either lean or normal weight in the metformin group and 37.8% being so in the clomiphene group. In the Neveu observational study, the mean BMI was
27.4 in the clomiphene group and 34.3 in the metformin group; [85] thus, the patient groups were purposefully different. In the Legro trial, clomiphene remained superior to
metformin across BMI strata but the mean BMI was 36. [86] In the most recent meta-analysis available, the effectiveness of metformin in subfertile women with PCOS was
evaluated.[87] Only randomized trials were eligible and the primary outcome was live birth. A total of 27 trials were identified. In therapy-naive women, no evidence of a difference
in live-birth rate was observed when comparing outcomes of metformin versus clomiphene, or metformin plus clomiphene versus clomiphene alone. In clomiphene-resistant
women, metformin plus clomiphene led to higher live-birth rates than clomiphene alone. They concluded that clomiphene was still the first-choice therapy for women with
therapy-naive PCOS; in clomiphene-resistant women, the combination of clomiphene plus metformin was the preferred treatment option.
Thiazolidinediones reduce hyperinsulinemia and hyperandrogenemia in some women with PCOS, and may induce ovulation.[88] Thiazolidindiones have also been shown to
induce ovulation in clomiphene-resistant subjects with greater efficacy than metformin. [89] Although both rosiglitazone and pioglitazone have little short-term risk, fetal safety has
not been established (pregnancy category C of the US FDA guidelines). If used, they should be discontinued as soon as pregnancy has been established.
Aromatase Inhibitors. Aromatase inhibitors induce ovulation by increasing FSH in a manner similar to that of clomiphene and their use has been advocated because of ease of
administration and potential superiority over clomiphene, given the lack of estrogen antagonistic effects. [90] However, in a prospective randomized trial comparing letrozole with
clomiphene, pregnancy rates were similar.[91] Although Novartis Pharmaceuticals (Basel, Switzerland) has warned against use of letrozole for ovulation induction (owing to
possible teratogenicity), a comparison with clomiphene did not demonstrate increased rates of major or minor malformations.[92]
Glucocorticoids. Glucocorticoids, such as prednisone and dexamethasone, have been used to induce ovulation. They lower androgens and also LH and may benefit some
clomiphene-resistant patients.[93] Enthusiasm for their use is dampened, however, by their potential adverse effects on insulin sensitivity and, therefore, prolonged use should be
discouraged.
Laparoscopic Ovarian Diathermy. Laparoscopic ovarian diathermy (LOD), an alternative to wedge resection, is also an option for clomiphene-resistant patients who are
unable to use FSH[94] and is associated with lower multiple gestation rates than gonadotropins. In this Cochrane Database Systematic Review article, there was no evidence of
a difference in live-birth rate and miscarriage rate in women with clomiphene-resistant PCOS undergoing LOD versus gonadotropin treatment. It appears to be more effective in
patients with high LH and significant reductions in LH and androgens have been shown following surgery. LOD restores menstrual regularity in 63-85% of women and the
beneficial effects on reproductive outcomes seem to last for several years in many women. [95] In a randomized trial comparing metformin versus LOD in clomiphene-resistant
women, ovulation, pregnancy and live-birth rates of 55.1, 13.4 and 64.5%, respectively, were shown 6 months after LOD, compared with rates of 54.8, 18.6 and 82.1%,
respectively, in metformin-treated patients.[96] While the ovulation rates were similar, the pregnancy and live-birth rates were higher in the metformin group. In the meta-analysis
of the role of metformin,[87] metformin led to higher live-birth rates than LOD. There was no positive effect on live-birth rate when metformin was added to LOD.
Lifestyle Modification & Bariatric Surgery
Lifestyle modifications resulting in weight loss can lead to ovulatory cycles and spontaneous pregnancy. If spontaneous weight loss cannot be achieved with diet and exercise,
bariatric surgery can be offered. In a group of 12 PCOS patients available for follow-up after bariatric surgery for morbid obesity, regular cycles were restored in all. [67] In a
similar study of 24 morbidly obese women with PCOS, all of whom were oligomenorrheic, Roux-en-Y gastric bypass restored regular menstrual cycles in all patients; five
women conceived.[68]
Critical Appraisal of the Treatment Options for Ovulation Induction in PCOS
Clomiphene citrate remains the mainstay of ovulation induction in this patient group, although with increasing obesity we are likely to see more clomiphene resistance. There is
a small risk of multiple gestation with clomiphene (mainly twins), with its attendant maternal and neonatal morbidity. It is quite possible that different populations, with differing
degrees of insulin resistance, respond differently to metformin. [83,86] In the authors view, and with critical appraisal of the available literature, it would seem that normal-weight
patients (BMI < 25) do not appear to need metformin, [82] while in patients who are overweight or mildly obese, metformin alone, if time permits, or metformin plus clomiphene,
may induce ovulation.[83,85] In the observational trial of Neveu et al., when analysis was performed according to BMI, ovulation rates were significantly higher on metformin in
patients with a BMI of 27-35, whereas for patients with a BMI of less than 27 or more than 35, ovulation rates were similar between clomiphene, metformin, or even the
combination.[85] It appears that in the more severely obese, even the combination of clomiphene and metformin may not induce ovulation. These patients present the greatest
challenge, as, for many, FSH treatment is both unaffordable and risky. Under these circumstances, off-label use of thiazolidinediones, along with clomiphene and metformin,
may result in ovulation and pregnancy (Nader S, Personal Observation).
Thus, when considering ovulation induction in patients with PCOS, the following would seem reasonable: lifestyle modification with diet and exercise is strongly recommended.
Clomiphene citrate is generally the agent of choice for ovulation induction. For patients who are overweight or obese, metformin 1.5-2 g is administered in combination with
clomiphene 50-150 mg to achieve ovulation. If clomiphene resistance (in thin or normal-weight patients) or resistance to metformin plus clomiphene is encountered, FSH
treatment is recommended. When FSH is used, a 'step-up' regimen is preferred in order to minimize the risks of multiple gestation and severe ovarian hyperstimulation
syndrome. In obese, insulin-resistant patients who are resistant to metformin plus clomiphene, off-label use of thiazolidinediones is also discussed and often used instead of
FSH. Side effects (weight gain) and fetal safety issues may deter some patients. If used, thiazolidinediones are administered along with metformin and, if the patient remains
anovulatory after 2-3 months, clomiphene is reintroduced. In nonobese women, dexamethasone is occasionally added to clomiphene, especially if the adrenal androgen
concentration is elevated. LOD might be offered to those who are resistant to or who fail clomiphene and, occasionally, as an alternative to medication-induced ovulation. The
role of aromatase inhibitors remains to be determined.
Expert Commentary
The common association of PCOS with the metabolic syndrome has brought international attention from a wide variety of sources and experts on the plight of women with this
syndrome. Emergence of clinical guidelines, evidence-based treatment decisions and randomized trials are welcome advances in the field of PCOS. Until recently, the focus of
treatment regimens was on the management of symptoms. However, given the long-term nature of this treatment, questions are being raised regarding long-term (as well as
short-term) safety. This aspect of the field is slowly evolving; it is extremely important and should be at the forefront of all treatment decisions. Invited commentaries, clinical
debates and a critical appraisal of the literature by knowledgeable physicians and medical societies will certainly help enhance the lives and well-being of patients with PCOS.
Five-year View
One of the reasons that progress has been slow and controversy abundant in this field has been the lack of recognition of the heterogeneity of the syndrome. The phenotypic
variety of PCOS relates to genetic and biochemical differences, compounded by environmental and even developmental factors. [97] The clinical expression of the disease
represents the final common pathway of these derangements. This more encompassing view of PCOS, as well as its origin, was recently explored and described.[98] It is likely
that this heterogeneity will be addressed more effectively and seriously in the next few years. For example, clinical trials will target specific populations and more efforts will be
made to understand the genetic, biochemical, environmental and developmental determinants of the disease in a given patient. In light of the epidemic of adolescent and
childhood obesity, management of PCOS in this age group will assume greater importance. More efforts will be made to delineate cardiovascular risk individually. Clinically
useful markers of this risk will be further developed and tested in this patient population, as will changes in risk markers with treatment. As we approach the 75th anniversary of
the early observations of Stein and Leventhal, these efforts will probably be well underway and progress is inevitable.
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• Large, randomized trial of ovulation induction in PCOS.
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• Explores and explains the origins and heterogeneity of PCOS.
Sidebar: Key Issues
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Polycystic ovary syndrome (PCOS) is characterized by anovulation, hyperandrogenism and cystic ovaries. However, the underlying pathogenesis is varied and
insulin resistance and obesity, while very common, are not universal.
Oral contraceptive pills (OCPs) and anti-androgens are commonly used for the treatment of PCOS symptoms.
Adverse long-term metabolic and cardiovascular outcomes may relate to both the underlying insulin resistance and obesity and, potentially, also to its exacerbation
by long-term treatment, such as with OCPs, in the predisposed individual.
Risk modification is the key to long-term management and should include weight-control efforts, exercise and the use of insulin-lowering and -sensitizing agents,
such as metformin, in the at-risk patient.
Anovulatory infertility is a common presentation of PCOS and is characterized by low follicle-stimulating hormone (FSH) availability and arrest of antral follicle
growth.
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Clomiphene citrate remains the mainstay of ovulation induction in PCOS.
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Addition of an insulin-lowering and -sensitizing agent, such as metformin, may improve ovulatory efficiency in the overweight and mildly obese clomiphene-
resistant PCOS patient.
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Ovulation induction using FSH injections carries risks of multiple gestation and severe ovarian hyperstimulation syndrome. A 'step-up' threshold, dose-finding
regimen is safer than the higher initial dose 'step-down' approach, and is the recommended protocol.
Other treatment options for anovulation include laparoscopic ovarian diathermy and, in the obese, bariatric surgery