女性癌症教學 Teaching and Research

1.Obesity
2. Hirsutism (excess hair growth) with elevated male hormone levels ( i.e. testosterone).
3. Irregular or absent menstruation since puberty.
4. Lack of ovulation and infertility.
5. Ovaries with many small cysts, hence the term polycystic.
6. Insulin resistance with a greater risk of developing diabetes.

b) Non Classical PCO or PCO variants.

This subtle condition is far more prevalent than the classical form of the disease and patients present with some of the features (1-6 above) but not all. Specifically these patients may be thin but still manifest aspects of classical PCO.

Patients with PCO have a disruption to several hormonal systems leading to an abnormal ovulation, hirsutism, and possibly insulin resistance.

a) Pituitary -There is an excess production of LH compared to FSH (greater than 3: 1) leading to disruption of the menstrual cycle and increased androgen (male hormone) production in the ovary.

b) Ovary-Increased production of estrogen without progesterone may lead to the development of a thickened uterine lining (endometrial hyperplasia) and possibly uterine cancer over many years. Testosterone production is also increased in the small cysts of the ovary and this may be converted to more estrogen in the fat cells.

c) Adrenal-An elevation in adrenal androgens (DHEAS) is seen in some PCO patients.

d) Insulin Resistance- This phenomenon relates to an insensitivity of the PCO patient to insulin requiring the body to produce a greater amount of this hormone to process a given amount of carbohydrate. Since insulin has the effect of increasing testosterone production in the ovary, a self-perpetuating cycle is produced.

There are several aspects important to the diagnosis of PCO:

a) History and physical examination (this will enable classical PCO patients to be differentiated from the non classical.
b) Hormonal testing including fasting glucose and insulin levels.
c) Ultrasound to visualize the ovaries.
d) Endometrial biopsy to exclude pre cancerous uterine conditions.

Treatment of PCO can take many forms including:

a) Weight loss (this may be difficult because of high testosterone levels.)
b) Regulation of menses may be accomplished with regular administration of progesterone or the use of an appropriate oral contraceptive (one low in androgens).
c) Ovulation induction with:
　

1. Clomiphene citrate.
2. Gonadotropins such as Follistim or Repronex with the occasional use of a GnRH agonist (Lupron)or antagonist (Antagon). Close monitoring to prevent hyperstimulation of the ovary is mandatory.
3. Dexamethasone may be used to suppress adrenal androgen production.
　

d. Insulin resistance may be treated with weight loss and Metformin (Glucophage)

e. Hirsutism- May be treated with an appropriate oral contraceptive preparation, Spironolactone, and cosmetic approaches such as electrolysis and laser.

f. Surgery- In refractory cases, laparoscopic surgery with a YAG laser may be used to reduce the ovarian production of testosterone.
Illustration of Polycystic Ovary

　

Medications, surgery, and weight reduction are common strategies to manage this syndrome.
Polycystic ovary syndrome (PCOS), formerly known as the Stein-Leventhal syndrome, was first described by Drs. Stein and Leventhal in 1935.¹
It is one of the most common endocrinopathies affecting women of reproductive age.^2,3 Most women who develop PCOS have oligomenorrhea or amenorrhea, hirsutism, obesity, and infertility.⁴ Another common finding in women with PCOS is a normal onset of menarche that is “frequently followed by painless, erratic menses.”³ PCOS is a familial disease in some cases.⁵ The syndrome is characterized by endocrinologic and reproductive abnormalities.^3,6

The prevalence of PCOS has been estimated to be between 2%–20%, depending on its definition.⁷ Utilizing the diagnostic criteria of ovulatory dysfunction, clinical hyperandrogenism (i.e., hirsutism) and/or hyperandrogenemia in women without hyperprolactinemia, congenital adrenal hyperplasia, or Cushing’s syndrome, one group of investigators estimated the prevalence to be approximately 4.6%. Knochenhauer and colleagues evaluated 369 women, of whom 148 blacks and 129 whites consented to participate.⁷ However, most epidemiological studies exclude women of diverse ethnic backgrounds and only include those who have visited their healthcare practitioner with complaints consistent with this condition.

The general therapeutic approaches to this disorder range from the use of medications (e.g., antiandrogens, oral contraceptives) that treat the clinical manifestations, to operative techniques (e.g., ovarian wedge resection and diathermy) to manage the physiological abnormalities, to weight reduction that restores ovulation.⁸

Pathogenesis

Various studies have found positive correlations between insulin and androgen levels.^9,10 Dunaif et al.⁹ demonstrated a significant positive relationship between unbound testosterone and insulin in obese women, which is similar to results from other studies in obese women with PCOS.^11,12 Investigators have shown that in vitro theca cell growth and production of androgen are stimulated by their binding of insulin and insulin-like growth factor 1 (IGF-1).^13,14

In obese women with PCOS, diazoxide administration for 10 days significantly lowered bound and unbound testosterone serum concentrations; this was mediated by decreased insulin plasma concentrations.¹⁵ Further support is given to the hypothesis of insulin-induced hyperandrogenemia from studies demonstrating that gonadotropin releasing hormone (GnRH) agonist suppression of testosterone and androstenedione does not affect insulin serum concentrations or insulin-stimulated glucose disposal.^16,17 It appears that insulin resistance is not mediated by androgen plasma concentrations. In fact, most evidence supports the hypothesis that hyperinsulinemia causes increased ovarian androgen production, which leads to hyperandrogenemia in women with PCOS.^16,18-21

Jarrett and coworkers²² studied the binding affinity of insulin to human ovarian membranes that contained granulosa and thecal cells, ovarian stroma, and connective tissue and concluded that there is “significant, high-affinity binding of insulin to human ovarian tissue.” Poretsky et al. found that insulin receptors are present in the human ovarian tissue that is composed primarily of stroma.²³ Ovarian stroma produces various steroids in vitro: androstenedione, dihydrotestosterone (DHT), estradiol, estrone, progesterone, and testosterone.²⁴

Another hypothesis for the etiologic basis of PCOS, put forth by Rosenfield and colleagues, involves cytochrome p450c17alpha.²⁵ An enzyme with dual functions, p450c17alpha converts progesterone to 17alpha-hydroxyprogesterone and 17alpha-hydroxyprogesterone to androstenedione through its 17alpha-hydroxylase and 17,20-lyase activity, respectively. Another enzyme, 17beta-reductase, converts androstenedione to testosterone.²⁶ Rosenfield and colleagues proposed that the abnormal enzymatic activity of cytochrome p450c17alpha leads to increased production of androgens within ovarian thecal cells. The hyperfunctioning of this enzyme may be due to excessive stimulation of thecal cells by luteinizing hormone (LH) or due to the thecal cells’ inability to be desensitized by LH.²⁵

Nestler and Jakubowicz reported that decreased insulin levels may indeed reduce p450c17alpha activity, either directly or indirectly, by reducing LH serum concentrations.²⁶

Pathophysiology

As the name implies, PCOS may be suspected based on the appearance of polycystic ovaries on ultrasound. However, this finding is not specific for PCOS, for polycystic ovaries are found in women who have hypothalamic amenorrhea and congenital adrenal hyperplasia.²⁷ In fact, many patients with PCOS do not have polycystic ovaries, and some women who ovulate normally and lack the characteristics that satisfy PCOS criteria may have ultrasound-identified polycystic ovaries.^27,28
A remarkable finding in women with polycystic ovaries is the greater-than-normal number of graafian follicles and the lack of mature or preovulatory follicles.⁴ This may reflect the early luteinization of follicles.⁴ The biochemical profile and histological findings do not correlate in women with PCOS,²⁷ nor does the ovarian appearance correlate with symptomatology.²⁷

Diagnosis

Table 1
PCOS Diagnostic Criteria for Research Purposes*

Listed from most to least important:

Hyperandrogenism and/or hyperandrogenemia

Oligo-ovulation

Exclusion of other known disorders (Cushing’s syndrome, hyperprolactinemia, congenital adrenal hyperplasia)

Possibly, polycystic ovaries on ultrasound

*Consensus reached by the National Institutes of Health/National Institute of Child Health and Human Development

Source: Based on reference 28

The exact diagnostic criteria of PCOS have not been clearly elucidated, despite a National Institutes of Health/National Institute of Child Health and Human Development conference held to reach a consensus on this disorder. Nevertheless, the conference participants concluded that PCOS should be defined by the following criteria for research, which are listed in order of importance: hyperandrogenism and/or hyperandrogenemia; oligo-ovulation; exclusion of other known disorders, such as Cushing’s syndrome, hyperprolactinemia, or congenital adrenal hyperplasia, and, possibly, polycystic ovaries on ultrasound.²⁸ Other laboratory findings and clinical manifestations may present which can prove helpful in making a diagnosis.
　

Laboratory Findings: There are numerous biochemical abnormalities in women with PCOS (TABLE 2). The laboratory parameters affected include gonadotropins, androgens, estrogens, insulin, and glucose.

Table 2
Abnormal Laboratory Findings in PCOS

Serum Concentration Elevations
‧ Testosterone (bound and unbound)
‧ Androstenedione
‧ Estrone
‧ Luteinizing hormone (LH)
‧ Insulin
‧ Glucose
‧ Prolactin
‧ Possibly, dehydroepiandrosterone (DHEAS)

Below-normal Plasma Concentrations
‧ Follicle-stimulating hormone (FSH)
‧ Sex hormone-binding globulin (SHBG)
‧ Possibly, dehydroepiandrosterone (DHEAS)

The pattern of gonadotropin (LH and follicle-stimulating hormone, FSH) secretion in women with PCOS differs from the normal menstrual cycle. The normal cyclic secretion of FSH and LH is absent.²⁹ There is an abnormal elevation in LH^9,10,29 in relation to consistently low levels of FSH throughout the cycle,²⁹ such that the LH/FSH ratio is greater in women with PCOS.^10,12,19,30 The elevated serum concentrations of LH ultimately result in increased production of estrogen, which has a negative feedback on FSH release.^31,32 When LH levels are elevated in women with PCOS, they approach the concentrations achieved during the normal midcycle LH surge and are greater than those normally found in the follicular phase of the menstrual cycle.^31,32

Elevated serum androgen concentrations, specifically testosterone and androstenedione, have been demonstrated in women with this disorder,^{9,12,18,19,30,33} and the source of the excess androgens are the ovaries.^4,27 Barbieri and colleagues conducted a controlled in vitro study of the effect of insulin release on ovarian stroma in women with hyperandrogenism. Their results demonstrated an increased secretion of androgens from ovarian stroma.¹⁸ Other investigators³⁴ tested the fluid from small ovarian cysts in women with PCOS and found a high concentration of androstenedione and no detectable estradiol-17beta or estrone. Cyst fluid containing a high amount of androstenedione and small amounts of estradiol and estrone is characteristic of polycystic ovary syndrome.³⁴ Higher serum concentrations of androstenedione^12,35 and of total and unbound testosterone (the biologically active moiety of testosterone that is not bound to sex hormone-binding globulin) were demonstrated in women with PCOS as compared to controls.^{9,30,33,36,37}

Some investigators^19,36 have found estrogen levels to be similar in women with and without PCOS. However, Lobo and colleagues discovered that women with PCOS had higher levels of unbound estradiol-17beta.³⁶ Also, higher-than-normal estrone serum concentrations appear to be a “usual abnormal finding” in women with PCOS.^9,30,33,37 The elevation in estrone levels may be the result of androstenedione aromatization.^30,35,38 The elevated levels of unbound estrone,³⁰ testosterone, and estradiol^38,39 are due to a reduction in sex hormone-binding globulin (SHBG) capacity.^30,39 The increase in unbound estradiol may be a causative factor of inappropriate gonadotropin secretion in PCOS.³⁹ Lower serum concentrations of SHBG in the PCOS group than in the control group has been reported.³⁰

Additionally, obese women with PCOS have significantly lower androstenedione plasma concentrations compared to nonobese women with PCOS. Obesity increases the aromatization of androstenedione and, therefore, the manufacture of estrone.^30,33,38 Obesity is also associated with reduced SHBG plasma concentrations.^30,38 The normal estradiol to estrone ratios are reversed in women with PCOS such that there is a greater amount of estrone than estradiol.¹⁹

In some reports, dehydroepiandrosterone sulfate (DHEAS) serum levels were not as significantly elevated in controls as in those with PCOS.^10,30,36,37 However, other studies demonstrated that DHEAS levels are lower in women with PCOS than in those without PCOS because DHEAS is secreted almost exclusively from the adrenal cortex. Therefore, increased androgen production by ovaries will lead to reduced androgen production from the adrenals, as signified by DHEAS. Hyperinsulinemia is also associated with lower serum concentrations of DHEAS.

Patients with PCOS have higher basal serum insulin concentrations than normal women.^10,12,19 Women with PCOS also tend to have a greater insulin response to the oral glucose tolerance test than those without PCOS.¹⁹ Women with PCOS have reduced insulin-stimulated glucose utilization³⁷ and require higher amounts of insulin to stimulate glucose disposal as compared to controls.³³ It is important to note that the insulin resistance happens in the face of normal glucose tolerance in nonobese women with this disorder; therefore, insulin resistance is not dependent on glucose tolerance^19,33,37 or obesity.^{9,10,12,19,33,37} However, obese women with PCOS have a greater degree of hyperinsulinemia than nonobese women with PCOS30 and obese normal women.^30,40 Also, the serum concentration of C-peptide is higher in obese women with PCOS than in normal obese women.⁴⁰ Insulin resistance in obese patients with polycystic ovary syndrome is an important determining factor of hyperinsulinemia.⁴⁰

Higher-than-normal fasting glucose serum concentrations³⁷ and more impaired glucose tolerance tests⁹ occur in obese women with PCOS versus obese women without this condition. The elevated plasma glucose concentrations appear to be secondary to insulin resistance in the periphery and in the liver,^11,37 since insulin is required for glucose uptake in the hepatic and peripheral tissue.⁴¹

Although its occurrence is uncommon, hyper-prolactinemia exhibited as galactorrhea may be a presenting feature of PCOS.^3,27,37

In summary, the abnormal laboratory findings that may be detected in women with PCOS are serum concentration elevations of testosterone (bound and unbound), androstenedione, estrone, LH, insulin, glucose, prolactin, and possibly DHEAS. Below normal plasma concentrations of FSH, SHBG, and possibly DHEAS may also be measured.
Clinical Manifestations: Common clinical manifestations of PCOS are listed in TABLE 3. Obesity is
not an uncommon finding.⁴ An estimated 50% of women with PCOS are obese—i.e., have a body mass index (BMI) greater that 27 kg/m².⁴² Those with obesity and PCOS increase their risk
of developing impaired glucose tolerance, whereas nonobese women with PCOS (and therefore insulin resistance) have in most cases, normal glucose tolerance.⁹ Obesity is associated with a reduced amount of insulin receptors, as well.¹²

Table 3
Clinical Manifestations of PCOS

Condition     Significance

Obesity    Occurs in 50% of patients; associated with increased risk of impaired glucose tolerance and reduced number of insulin receptors

Amenorrhea/ Oligomenorrhea    Consistent clinical features of PCOS; may result from high testosterone plasma concentrations

Infertility    Occurs in 75% of patients; secondary to ovulatory failure

Hirsutism   Inconsistent manifestation; may be due to increased peripheral androgen activity at pilosebaceous units of skin

Acanthosis nigricans Associated with obesity; due to insulin resistance

Acne/alopecia    Associated with hyperandrogenism in PCOS

Amenorrhea and oligomenorrhea are consistent clinical features of PCOS and have been hypothesized to occur secondary to high testosterone plasma concentrations.⁴³ However, not all women exhibit dysfunctional uterine bleeding; some do ovulate and have regular menstrual cycles.⁴

Infertility has been documented as a clinical feature in 75% of women with PCOS.⁴ The infertility is secondary to ovulatory failure, which is indicated by low serum concentrations of pregnanediol.³⁵ Pregnanediol is formed during the metabolism of progesterone and is found in the urine during pregnancy and in certain phases of the menstrual cycle.⁴¹ Nevertheless, the normal effect of estrogens on gonadotropins is maintained in women with PCOS, supporting the thought that the hypothalamic and pituitary responses to estrogen are not a cause of anovulation in PCOS.³⁵ Furthermore, progesterone serum concentrations (normally elevated in the luteal phase of the menstrual cycle) and the presence of amenorrhea and/or oligomenorrhea determine chronic anovulation.³³ Also, irregular patterns of FSH secretion may be due to abnormally elevated estrogen serum concentrations and a causative factor in anovulation.³⁴

The appearance of hirsutism in women with PCOS may reflect an increased amount of peripheral androgen activity at the pilosebaceous units of the skin.³⁶ The degree of hirsutism can be rated according to the Ferriman-Gallwey system, from which a score of at least 8 indicates hirsutism.⁴⁴ Hirsutism is not a consistent manifestation of PCOS; women with hyperandrogenemia do not always exhibit clinical hyperandrogenism.³³

Acanthosis nigricans (papillomatous hyperpigmentation of the epidermal skin layer, especially in the axilla regions and the neck) appears to be associated with obesity in women with and without PCOS^30,37; insulin resistance is the underlying cause of this condition.³⁷ This skin lesion can also occur in nonobese women.^9,30 Women with PCOS and clincially evident ancanthosis nigricans have higher insulin serum concentrations than do women without this dermatologic problem.⁹ Nevertheless, hyperinsulinemia can exist in women with PCOS in the absence of acanthosis nigricans and obesity.¹⁰ A study performed by Dunaif and her colleagues showed that acanthosis nigricans occurred in the majority (14 out of 18) of obese women with PCOS.⁹ Other clinical features associated with hyperandrogenism in PCOS include acne and alopecia.3

Morbidities Associated with PCOS
PCOS can result in significant morbidities, such as ovarian cancer, coronary artery disease, and impaired fertility (TABLE 4). Obesity in women with PCOS is usually exhibited as an increased waist to hip ratio, which predisposes women to metabolic health risks.³ In fact, it has been estimated that 20% of obese women with PCOS develop diabetes mellitus or impaired glucose tolerance (IGT) by their third decade of life.^9,37 High insulin serum concentrations increase the risk of developing diabetes mellitus (DM) and therefore, coronary artery disease.

Table 4
Morbidities Associated with PCOS

‧ Diabetes mellitus

‧ Coronary artery disease
           Myocardial infarction
           Unstable angina
           Congestive heart failure

‧ Cardiovascular and metabolic disorders
           Hypertension
           Type 2 diabetes
           Impaired glucose tolerance

‧ Increased risk for endometrial cancer

‧ Possible association for ovarian cancer

Source: Based on references 6, 9, 37, 45, 46

Cardiovascular and metabolic disorders, specifically hypertension, type 2 diabetes mellitus, and impaired glucose tolerance, can occur in women with PCOS at a greater rate than in normal women, some investigators believe. This increased risk for complications is due to the insulin resistance and obesity that are common characteristics in women with PCOS. PCOS also has been shown to reduce HDL and increase triglyceride plasma concentrations, which further compounds the cardiovascular risk in these women.⁶ Young women with PCOS need to be closely monitored for the development of impaired glucose tolerance and diabetes mellitis. DM is a major contributor to the risk of coronary artery disease, which can manifest as myocardial infarction, unstable angina, congestive heart failure, and other life-threatening conditions.⁴⁵

Hypertension is another complication of PCOS. Young women with PCOS generally have blood pressure readings within the normal range; with increasing age, however, systolic blood pressure also increases. The elevation in systolic blood pressure is higher in women with PCOS than in age-matched controls.⁴⁵

Women with PCOS are at increased risk for endometrial cancer secondary to prolonged, unopposed estrogen stimulation of the endo-metrium.⁶ An association between ovarian cancer and PCOS also has been suggested by Schildkraut and colleagues.⁴⁶

Treatment

Generally, therapy attempts to relieve the particular complaint of the patient, which can vary from infertility and/or menstrual dysfunction to physical appearance; on the other hand, if medical treatment to enhance insulin sensitivity is begun early, then the long-term outcome would be much improved.³
Weight Reduction: The first line of therapy in obese women with PCOS is weight reduction to reduce hyperinsulinemia and its effects on hyperandrogenemia. Weight reduction in obese women increases SHBG and decreases insulin resistance, leading to lowered androgen plasma concentrations. Successful obesity management may restore ovulation in women with PCOS. Other benefits are associated with decreasing insulin and androgen serum concentrations, including improvement of hirsutism and acanthosis nigricans.³
Antiandrogens: Spironolactone blocks the binding of DHT (the active moiety of testosterone) to androgen receptors, causing regression of hair growth. This agent also decreases p450c17alpha activity, which reduces androgen production. Given at a daily divided dosage of 100–200 mg for 6–12 months, spironolactone has been shown to reduce hair growth.^47-48 Adverse effects of spironolactone include hyperkalemia, dehydration, and hyponatremia.⁴⁹

Finasteride (4-azasteroid), a 5alpha-reductase inhibitor, reduces the conversion of testosterone to DHT, thereby decreasing the binding of DHT to the androgen receptor.^50,51 It has been shown to be as effective as spironolactone in decreasing the hair shaft diameter.⁵⁰ PCOS patients treated with finasteride for 12 months had a statistically significant reduction in their Ferriman-Gallwey score, with substantial improvement noted in their hirsutism scores by 3 months of treatment and maximal response at 6 months. The most common adverse effect was mild and transient nausea.⁵¹

The antiandrogen flutamide competitively inhibits binding of testosterone to androgen receptors.⁴⁹ It is primarily used in the treatment of prostatic carcinoma. This agent should only be used in women with PCOS when other therapies for hirsutism did not prove to be effective.
Ovulation Inducers: A number of agents may be considered for inducing ovulation in women with PCOS.
‧ Oral contraceptives: Various reports demonstrate the beneficial effects of using an oral contraceptive (OC) in women with PCOS. OCs have been postulated to decrease LH, increase hepatic SHBG production, and inhibit receptor binding of 5alpha-reductase and androgens.^52-53 Givens et al.⁵⁴ used an OC containing 2 mg norethindrone and 0.1 mg mestranol, given on a cyclic basis to a 17-year-old woman with PCOS and a stromal luteoma. The OC decreased her plasma concentrations of androstenedione and testosterone, and improved her acanthosis nigricans almost to the point of disappearance.

It is important to use OCs with progestational components with minimal androgenic potency, such as those with desogestrel or norgestimate. Agents with progestins of high androgenic potency—i.e., levonorgestrel and norethindrone—should be avoided in women with PCOS. These agents have negative effects on the lipid profile such that HDL decreases and LDL increases, whereas desogestrel and norgestimate have positive effects on lipids.⁴⁹ Oral contraceptives also help treat acne and hirsutism and prevent ovarian and endometrial cancer.³
‧ Cyproterone acetate: A common agent for treating PCOS outside the U.S., cyproterone acetate (CPA) has progestinic, anti-androgenic, and mild glucocorticoid activity. It suppresses ovarian steroidogenesis, decreases plasma testosterone concentrations, and induces hepatic metabolism. Amenorrhea may result if CPA is used for longer than the first 10 days of the OC pill cycle. (It is manufactured in a combination tablet with ethinyl estradiol and as a single agent for the treatment of prostate cancer.) Weight gain and edema can result and may be due to its glucocorticoid activity.⁵⁵
CPA has been used successfully in combination with ethinyl estradiol and leuprolide acetate to reduce hirsutism in women who did not respond to OC treatment alone.⁵⁶ The use of an OC tablet containing ethinyl estradiol-CPA with or without a GnRH agonist caused significant reductions in Ferriman-Gallwey scores, estradiol, testosterone, androstenedione, and 17-OH progesterone serum concentrations. The effect on gonadotropins was more pronounced in the group that received the GnRH agonist. There was a greater decrease in hirsutism in the obese and hirsute groups in this trial. GnRH agonist therapy should be reserved for use in obese women with severe hirsutism because of its expense and greater effectiveness in this patient population.⁵⁷
‧ Clomiphene citrate: A racemic compound with estrogen agonist and antagonist activity, clomiphene citrate’s activity is determined by the dose used and by the recipient’s endogenous estrogenic status.⁵⁸ It induces ovulation by increasing the pulse frequency of GnRH (i.e., the occurrence of increased GnRH release from the hypothalamus). It is effective in women with PCOS because

Clomiphene citrate can be a first-line treatment for stimulating ovulation in women with PCOS.

it decreases LH and increases SHBG serum concentrations.⁵⁹Therapy is initiated at an oral dose of 50 mg per day for 5 days in the early follicular phase. The dose can be increased to 100 mg and then to 150 mg if ovulation fails to occur with the lower dose. The lowest possible dose should be used. Generally, if the 150 mg dosage is not effective, then another therapy is instituted.⁵⁸

Adverse effects include hot flushes, nausea, vomiting, and ovarian hyperstimulation. Interestingly, one isomer of CC is structurally related to diethylstilbestrol, and CC should not be used in early pregnancy. However, CC is still considered an effective first-line treatment for stimulating ovulation in women with PCOS.⁵⁸
‧ Gonadotropins: Human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) are used to stimulate ovulation in women who do not respond to clomiphene citrate. When given in combination with CC, hCG can be administered at a dose of 5000 IU to induce ovulation. Clomiphene’s use with hMG is usually to reduce the dose of gonadotropin given in order to decrease the risk of hyperstimulation and high-order multiple pregnancy.⁵⁸ In one study,⁶⁰ a total dose of 300 IU of hMG was initiated for 3 days, then the dosage adjusted based on the rise of serum estradiol concentrations. When a leading follicle obtained the desired size, then 10,000 units of hCG was administered intramuscularly to achieve ovulation.
‧ GnRH agonists: Taskin and colleagues evaluated the effect of subcutaneously administered goserelin acetate and OC treatment, versus ovarian cauterization, on the biochemical profile of women with clomiphene-resistant PCOS. Both modalities decreased LH, FSH, androstenedione, and testosterone, and increased SHBG serum concentrations. However, the oral combination caused a greater reduction in LH and elevation in SHBG,⁵⁷ was less invasive and expensive, and is not as likely to cause infertility as a consequence of surgically acquired periovarian adhesions.

The available GnRH agonists in the U.S. are goserelin acetate, leuprolide acetate, and nafarelin acetate.^49,61 Adverse effects include decreased bone mineral density with prolonged use, hot flashes, decreased libido and ovarian hyperstimulation syndrome (OHSS). Abdominal ascites and ovarian enlargement are the main characteristics of OHSS. The acute fluid overload can cause respiratory distress and even pulmonary edema. Renal failure, stroke, and death can result from this dangerous adverse effect, particularly in women with PCOS.⁶² These agents are contraindicated in pregnancy because of its teratogenicity in animals.^49,61
‧ Glucocorticoids: Glucocorticoids are an option for adjunctive therapy to induce ovulation in women with PCOS who do not respond to clomiphene alone. Glucocorticoids reduce adrenal androgen secretion, which increases the likelihood of ovulation and pregnancy.⁶³ Singh and colleagues evaluated clomiphene and dexamethasone in women with PCOS. Therapy was initiated at a CC dose of 50 mg plus dexamethasone 0.5 mg on day 5 of the menstrual cycle. The dose of

Therapies for PCOS aim to reduce androgen secretion, improve fertility, and manage insulin resistance.

clomiphene was titrated to 150 mg per day in women who did not respond to lower doses. The concurrent use of clomiphene and dexamethasone in women with clomiphene resistance resulted in ovulation in 88.8% of the women with PCOS.⁶⁴
Insulin Sensitizers: Insulin sensitizers—specifically, metformin and troglitazone^65-69—have been used in women with PCOS with positive results. However, troglitazone has been removed from the market because of hepatotoxic effects that caused liver failure and death.

Metformin is a biguanide antidiabetic agent that is not FDA-approved for use in the treatment of PCOS. Nevertheless, it is beneficial in managing the insulin resistance that is a common characteristic in these patients. Metformin does not affect insulin secretion, but it does decrease hepatic glucose production and improve peripheral glucose utilization.⁴⁹ It has been demonstrated to reduce unbound testosterone and androstenedione,^65,67 total testosterone,⁶⁶ and fasting insulin serum concentrations,⁶⁷ and increase SHBG^65-66 and FSH⁶⁷ plasma levels. Its positive effects on insulin resistance and reduced free testosterone have helped to increase successful pregnancy rates in women with PCOS.⁷⁰

A dose of metformin at 500 mg given three times daily has been shown to be effective when used in managing PCOS.⁷⁰ Metformin’s most common side effects include nausea, diarrhea, and abdominal discomfort. Patients with renal insufficiency should not take this medication because of the increased risk of lactic acidosis. Metformin should not be used in women who are pregnant.⁴⁹
Surgery: In general, operative techniques to manage this syndrome are used following treatment failure with clomiphene, gonadotropin, and LHRH. Ovarian wedge resection was the first surgical maneuver described. It is successful in restoring ovulation because of the destruction of excess ovarian stroma, which decreases the amount of tissue available for androgen conversion to estrogen. However, this procedure is associated with a high risk of periadnexal adhesion formation.⁷¹

Unilateral oophorectomy should be restricted for use in women with concomitant ovarian pathology. Fortunately, this procedure does not cause periadnexal adhesion formation.⁷¹ Ovarian drilling by laparoscopy is also known as laparoscopic ovarian diathermy, laparoscopic ovarian electrocautery, and laparoscopic electrocoagulation. An electric current is used in this procedure, causing release of follicular fluid that contains large amounts of androgens. Risks of this surgery include thermal injury to surrounding tissues, periadnexal adhesion formation, and premature ovarian failure.⁷¹

The Pharmacist’s Role

Pharmacists are ideally situated to aid the healthcare team in instituting cardiovascular preventive measures in women with polycystic ovary syndrome. Women who are obese can be counseled by pharmacists in techniques for weight loss and assessed for possible adverse effects from treatment. Pharmacists in an outpatient setting are able to remind patients on a regular basis about the importance of exercise and meal planning to reduce weight and improve their lipid profile.

Counseling patients about preventing hypertension should include instructions on implementing a low-salt diet, an exercise regimen, maintaining a nonobese weight, and cessation of smoking, when applicable. These are necessary components of a pharmacist’s service to patients with polycystic ovary syndrome.

Conclusion

According to one source, “PCOS is a fugitive syndrome with limits less well defined than those of the Sahara or Sudan.”⁷² Recent literature supports the role of hyperinsulinemia as one of the major pathogenic factors causing the hyperandrogenic manifestations associated with polycystic ovary syndrome. Healthcare practitioners must be aware of the morbidities associated with insulin resistance, and hence PCOS, in order to help prevent their occurrence. Therapies for women with polycystic ovary syndrome target reduced androgen secretion, regulation of gonadotropin release, improvement of fertility, and management of insulin resistance. The newest agent, metformin, has been demonstrated to improve all of the aforementioned parameters as a solo agent for managing PCOS.

Oral contraceptives are useful in hirsute women who do not want to conceive a child. Adjunctive management of hirsutism includes hair removal with depilatories, shaving, electrolysis, and the use of medical therapy as discussed above. If a woman is not hirsute and does not want to become pregnant, use of medroxyprogesterone acetate (MPA) for 10 days each month is a necessity to cause withdrawal vaginal bleeding. The benefit of this action is to prevent endometrial hyperplasia, which can lead to endometrial cancer.⁴¹

If pregnancy is desired, then clomiphene citrate is the first line-therapy. If clomiphene does not work, then use of a GnRH agonist is a reasonable option after a trial of gonadotropin. Other options for inducing ovulation include glucocorticoids and metformin. Cauterization or laser may be utilized for ovarian drilling to induce ovulation in women who do not respond to hormonal treatment. However, ovarian adhesions from surgical procedures is a common occurrence.

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