What Are The Best Treatment Options Suited For You? Some Guidelines to the Treatment of PCOS

There is no unanimity in the treatment of PCOS. Many authorities differ in some aspects of treatment. In general, one should consider your main complaint in directing your treatment. 

1) Acne and/or hirsutism and alopecia. These may occur as one or a combination of symptoms.
2) Uncontrollable appetite and weight gain- often symptoms of hypoglycemia after eating a carbohydrate-rich meal. This may be associated with difficulty in losing weight, craving for carbohydrates, and loss of self esteem.
3) Infertilty associated with erratic, sometimes heavy, and infrequent menses. 4) Miscellaneous
         Some major presenting complaints may occasionally include
               nipple discharge
               emotional dysfunction
               recurrent miscarriage rate
               pelvic pains

The following statements are a general consensus and my personal view, but takes into account the establishment of a correct diagnosis of PCOS, the probability of combined complaints, and the presence or absence of a significant associated adrenal androgen hormonal production.


1) SKIN MANIFESTATIONS
a.) Acne

Many women with PCOS respond to oral contraceptives (OCs) alone when the acne is mild to moderate. Most OCs are adequate, but some may actually not be effective or may worsen the acne. It is now established that the 3rd generation of OCs, particularly those using norgestimate as the progestin (progesterone) component, have been found to have no androgen (male hormone exacerbating) effect on the pilosebacious unit of the skin. Sometimes switching to this form of OC may be all that is needed in improving acne. In moderate to severe acne it is helpful to administer an antiandrogen, such as the most commonly used in the USA, spironolactone (Aldactone), in a twice a day dosage of 50-75mg. (total daily dose of 100-150mg). With this regimen most women start noting improvement in the cystic acne 3-6 months after initiating treatment.


b.) Hirsutism

It is the experience of most endocrinologists that hirsutism is poorly controlled by the administration of OCs alone. Perhaps 10-15% respond, but most require the use of OCs combined with spironolactone. Where the hirsutism is moderate to severe, a total daily divided dosage of 200mg of spironolactone is necessary. Response to treatment is slower than that of acne and usually 9 months of treatment are needed to demonstrate significant improvement. The latter may be manifest as a reduction in the need for electrolysis, and the observation that the hair that does return is finer and lighter, signifying reduction in the width of the hair diameter. Duration of treatment may vary, depending on desire for fertility in the near future, and response to treatment. A time frame of at least 3-4 months is suggested prior to attempting fertility after the use of spironolactone.

Other antiandrogens are also available. From a personal view, I rarely employ flutamide because of the potential of rare but serious liver toxicity. Outside the USA, there are good results obtained equal to and occasionally reported even superior to the combination of OCs and spironololactone, by the administration of Diane (a combination of an estrogen and the antiandrogen-progestin called cyproterone acetate). This drug is NOT FDA approved in the USA. In view of the potential for causing ambiguous male genitalia in a male fetus, I have great concerns about the use of finasteride (Proscar) in the treatment of skin manifestations in PCOS. Reports have indicated some improvement in hirsutism with insulin sensitizing agents in PCOS, but I have not found them to be greatly effective in the treatment of hirsutism as the main complaint. 

In patients who also have a major adrenal “component” in PCOS and who are concerned about hirsutism, the use of glucocorticoids such as a relative low-dose dexamethasone regimen has been reported for a number of years. While low-dosage dexamethasone (0.25mg before retiring) may be used in some patients, the experience of many experts in this field is that cortisone-like drugs are not very helpful in the treatment of hirsutism in the majority of patients, despite reduction of blood androgens, and should probably be employed in patients with infertility with an associated adrenal factor. The other obvious concern is the tendency to increased weight and insulin resistance which may be aggravated in such dexamethasone-treated patients. There are data indicating a probable role of OCs on reducing adrenal androgen production. The role of spironolactone on adrenal androgen production is less clear and an area for further research.
Patients with severe hirsutism of ovarian origin have been reported to respond to treatment with a GnRH agonist combined with OCs. This is done in the most refractory patents who do not respond to other forms of treatment. Monotherapy with a monthly injection of a GnRH agonist without OCs may induce 4-8% trabecular bone loss after 6 months and should not be employed.

Local treatments other than electrolysis now include improved laser techniques and the introduction of topical Vaniqa cream for facial hirsutism. Definitive results of these modalities require further comparative studies. 


c.) Alopecia

This is probably the most difficult symptom of the skin manifestations to treat in PCOS. It takes into account genetic, local, age-related, nutritional and hormonal factors. Exclusion of other disease entities, particularly thyroid disease and anemias, is essential. Adequacy of protein intake is important and supplementation with folic acid, zinc, B-12 and others may be considered. Alopecia as the presenting symptom in PCOS is not common, but its frequency from a number of investigators indicates that it may vary from 15-40% of all women with PCOS, independent of their body weight. 
The treatment options are similar to those of women with moderate to severe hirsutism (see above). The combined daily use of 200mg spironolactone and Ocs are needed to reduce further hair loss. 

Once there is alopecia secondary to androgen excess, regrowth of scalp hair is unusual with treatment. Some regrowth of fine hair may be noted occasionally but it is not common. Early recognition of this symptom in women requires rapid evaluation and treatment. The use of other treatments such as finasteride with OCs has been used but little data supports this as effective therapy. There are no data of finasteride treatment in women with PCOS and alopecia. Several investigators outside the USA have added cyproterone acetate in various regimens to women with androgen excess, and modest improvement in scalp hair has been noted in more than half of the 20 or so patients that have been followed in my practice. Authorities have differed about the effectiveness of the antiandrogenic effect of spironolactone as compared to that of cyproterone acetate. The latter is probably equal in effectiveness to the action of spironolactone, while some have reported that it may be minimally more effective in the treatment of hyperandrogenic women.
2) OBESITY, INCREASED APPETITE, CARBOHYDRATE CRAVING AND SYMPTOMS OF HYPOGLYCEMIA

These are common presenting complaints and a major index of very probable insulin resistance, elevated insulin levels and the sequelae of the hyperinsulinism. It may be associated with mood fluctuations, sugar-craving, increased appetite, possible fluid retention and evidence of abnormalities in lipids, triglycerides, and impaired glucose tolerance (IGT). The patient often notes the frequent association of the onset of significant weight gain with increased complaints of menstrual abnormalities, and skin manifestations.

Simply put:

Obesity= usually already signifies insulin resistance. The resulting drop in the androgen buffer sex-hormone binding globulin produced by the liver (SHBG) by increased circulating insulin levels compounds the effect of increased active testosterone resulting from the increased insulin and the relative ineffectiveness of insulin in influencing glucose metabolism in muscles, fat tissues and liver causing a relative “insensitivity” to insulin. Insulin has a unique effect in stimulating ovarian hormones in PCOS which are already stimulated by higher brain center mechanisms leading to higher stimulation of luteinizing hormone (LH) pulses which stimulate excessive ovarian androgen production.

Thus, LH ===========>
and INSULIN==========> both stimulate testosterone and other androgens from the ovaries, leading to local effects on the ovaries and manifestations on the skin and menstrual cycles.

In women with PCOS...........................

Insulin==> stimulates appetite and particularly a sugar craving ==> ingestion of food rich in carbohydrates elicits an over-response of insulin==>drowsiness, lack of concentration, possible sweats and tremulousness> further craving to thwart the above with carbohydrates etc. A vicious cycle thus ensues, which leads to further weight gain, emotional distress and the many symptoms and signs of PCOS, which may in time lead to metabolic and cardiovascular abnormalities. These may occur in genetically predisposed women with PCOS, particularly those with a family history of type 2 diabetes mellitus. The multi-genetic factors as well as specific gene studies involving the insulin receptor gene area are under intensive investigation in several centers including the Mount Sinai School of Medicine. 

Clearly, the primary treatments are weight reduction, and behavioral modifications including exercise and eating patterns. This is easy to direct, but frequently difficult to adhere to. Obesity reinforces the genetic predisposition to hormonal and menstrual abnormalities. The benefits of weight loss, which include reduction of carbohydrates and small frequent amounts of food throughout the day, include the following:

a.) reduction of circulating insulin levels
b.) reduction of SHBG with a subsequent
c.) reduction of active androgens levels.
d.) allowing for more adequate insulin action at receptor sites and reducing insulin resistance
e.) reduction of elevated serum lipids and triglycerides
f.) enhancing the probability of more regular menstrual patterns and fertility. 

Many of the above effects can be achieved with a modest 5-7% reduction in body weight. An experienced nutritionist is most helpful in achieving these goals, and start a reversal of the vicious cycle induced by obesity, with a view to prevent some of the potential metabolic and cardiovascular complications.

The use of insulin-sensitizing agents in the treatment of women with PCOS has been beneficial in numerous reports that have amassed in the medical literature for the past 7-8 years. Not all agree on its mechanism of action or its indications but it has frequently been helpful in achieving more regular menstrual cycles and reducing circulating androgen levels. Since troglitazone (Rezulin) has been removed from the market, the one agent which is widely used in improving insulin sensitivity in PCOS is metformin (Glucophage). There are several other drugs in the family of thiazolidinediones to which troglitazone belongs, but they have not as yet been described in the literature in the treatment of PCOS. Investigators are studying their effects in women with PCOS and these drugs (Actos, Avandia) have been available in the treatment of type 2 diabetes mellitus for the past several years. Preliminary reports indicate that D-Chiro-inositol may be an effective mediator of insulin action in women with PCOS. It is in the third phase study for FDA approval now, and appears to be promising and virtually free of side effects. Data indicate that it has great potential in improving ovulatory function and decreasing serum androgen concentrations, blood pressure and plasma triglyceride concentrations. 

Metformin is used by a number of endocrinologists with success in triggering a series of events which may lead to improved menstrual cyclicity and possible fertility. It is not for everyone. Having PCOS does not imply a knee-jerk reaction in using this drug. A number of prominent experts do not use this drug, and prefer other treatments for menstrual dysfunction and reduction of ovarian androgen production. It is not the drug of choice for a woman suffering from the skin manifestations of the syndrome, or women with kidney disease. The potential gastrointestinal side effects appear early and frequently diminish after 6-8 weeks of use. These include bloating, nausea, vomiting, flatulence and diarrhea. It is helpful to realize that every person taking the drug reacts differently. Some women are unable to tolerate it at all, while others have few if any side-effects. It should be helpful to know that it is the most widely used oral agent in the adult with type 2 diabetes mellitus, and millions of patients are on the drug. The vast majority of women (>90%) with PCOS that I see stay with it, and take the medication with meals, and in divided doses. I find it useful to start the patient slowly with one tablet of 500mg with breakfast. Even here, some women have to cut down to a half a tablet (250mg) with food, and up the dosage slowly. Since the optimum dosage is 1500-2000mg a day in divided doses, the increase in the dosage depends on the initial tolerance to the 500mg tablet. Most frequently, another 500mg tablet is added to the evening meal, when side effects are minimal. Usually at the 500mg twice-a-day dosage, the patient is experiencing mild weight loss, and may have less appetite and carbohydrate craving, a sense of well being, and fewer hypoglycemic reactions after eating. This is a good sign and indicates reduction of the hyperinsulinism and may be the trigger for a substantial emotional and physiological boost to the patient. If fertility is not desired, precautions should be taken by the patient while taking the drug. The optimum dosage is then used when side effects are less, and the drug is tolerated. The drug may be raised gradually to 1500 and then 2000mg daily in divided doses with breakfast and dinner. In women who are on a strict low carbohydrate diet (<50gm a day), the potential for hypoglycemia may occur, although the drug manufacturer states it does not cause hypoglycemia. I have seen this in at least 5 women on the drug and this must be recognized. The other precaution is to stop the drug for 24-48 hours when using contrast dye such as in a CT study. The duration of treatment and the potential of reducing later complications are not known. Years of study will answer that, but this drug and others “in the pipeline” may play a significant role in this most important issue.

There is an important issue in the treatment of the hyperinsulinemic patient who has erratic menses but also is distressed by severe acne and/or hirsutism, or alopecia. If the patient is infertile and wishes to conceive, monotherapy with metformin and perhaps in combination with clomiphene citrate (Clomid) is an initial option. However, if fertility is not an issue at the time of the initial consultation, one may consider “triple” therapy, i.e., metformin combined with Ocs and spironolactone when the skin manifestations are disturbing or severe. This has been used by Dr.John Nestler (Personal Communication) and I also have found it useful in the management of these women, with little additive side-effects of this combination therapy.

3) INFERTILITY ASSOCIATED WITH ERRATIC, SOMETIMES HEAVY, AND INFREQUENT MENSES

The treatment of the infertile patient with PCOS, and/or those with heavy menses and intermenstrual (dysfunctional) bleeding is quite varied and depends on a number of factors. 

These include a history of prior pregnancy, spontaneous or induced, the exclusion of the “male factor”, evaluation of the integrity of the fallopian tubes and endometrial lining of the uterus (ultrasonography is useful here), exclusion of local diseases including adhesions, endometriosis and uterine fibroids, cervical mucus disturbances and exclusion of associated systemic and hormonal disturbances (thyroid diseases as well as disorders of prolactin secretion) and other entities. Many of these should be evaluated by a competent gynecologist and/or reproductive endocrinologist and often a team effort is necessary in the achievement of fertility in such a patient.

Specific areas of treatment options in the patient who has not responded to standard regimens of weight reduction, or clomiphene citrate is discussed by other physicians in this seminar. My personal view is that following a careful pelvic ultrasound, and yes, the exclusion of pregnancy in an amenorrheic patient, endometrial shedding is indicated with a progestin (often Provera 10mg daily for 7-10 days). Following a withdrawal bleed which may be heavy, the patient who has significant hyperinsulinism is started with a trial of metformin (see above). In 3 months of treatment, the success or absence of a response to metformin will be noted. If ovulation does not occur, and this may be followed by home testing, basal body temperature curves and most useful, the determination of a serum progesterone level on day 21-23 of the menstrual cycle, the addition of clomiphene citrate 50mg on days 5-9 of the next cycle is the next step. Reports indicate that the vast majority of patients ovulate with this regimen and hopefully pregnancy may be achieved over the next few months. Although there are no reports of teratogenicity with metformin, the drug is stopped once pregnancy is detected.

A previous statement was made regarding the possible addition of a small dose of dexamethasone (usually 0.25 mg at bedtime with some food) in those women with PCOS who have a significant “adrenal factor”. This may be added to the metformin-clomiphene citrate regimen or with clomiphene citrate alone in attempting to improve the chance for achieving fertility. Again, after pregnancy is achieved, the dexamethasone should be discontinued.

It should again be stressed that such treatments are not universally performed, and time will tell whether the role of insulin-sensitizing agents should be the first choice in the initial treatment of infertility in SELECTED women with PCOS.
4) MISCELLANEOUS

There is a subset of women with PCOS who may present with nipple discharge (galactorrhea) usually in association with infrequent menstrual cycles, and hirsutism. This is usually secondary to elevation of circulating prolactin, and the frequency of this subset may range from 7-10% of afflicted women with PCOS. In these instances the pituitary cells that secrete prolactin (lactotropes) are hyperfunctioning and the presence of a small pituitary microadenoma may or may not be found on MRI testing. The indicated treatment is bromocriptine (Parlodel), a dopamine agonist, which reduces serum prolactin and improves menstrual function and also mood disturbances secondary to the hyperprolactinemia. After a 2-3 month course of bromocriptine, the effectiveness of treatment is assessed and if desired pregnancy is not achieved, additional options listed above may be employed in combination with the bromocriptine treatment. Parenthetically, elevated serum prolactin levels may be found on testing without the presence of galactorrhea. It is necessary to exclude medications that are being taken by the patient which may increase prolactin levels (Thorazine, Compazine, and to a lesser extent Prozac, verapamil etc.).

Mood swings and depression are not infrequent in women with PCOS. These often are a result of feelings of lack of self-esteem and may also reflect hormonal changes (including hyperinsulinism) in the syndrome. Occasionally the drugs used in the treatment of PCOS may worsen these symptoms and switching OCs, or using a different progestin may be helpful. Fluctuations in mood as well as reduction in libido may occasionally occur with spironolactone therapy and adjustment of the dose employed or cessation of the drug may be necessary. The treating physician(s) takes into account this association of mental status of the patient, the hopes and ambitions, and with empathy, encouragement and skill will attempt to guide the woman to a wise choice of treatment of this multivaried syndrome. On the other hand, the patient must realize that the natural history of this syndrome has as yet not been defined. The syndrome is one that may affect reproductive potential and does have a relatively high incidence and risk for the development of glucose abnormalities, but the risks of cardiovascular disease are not yet conclusively proven. One may read abstracts and articles of relatively small series of patients (< 50 patients) where the authors may conclude without numerical power of statistics that are necessary for valid interpretation, invalid conclusions about risks which may not necessarily be true. It is wise, however, to avoid any aspects of continued obesity, which is well known to be associated with many complications, whether the patient has PCOS or not. Genetics is the key......and this is the major player in any person’s potential for the development of disease. Interventions which may modify the genetic predisposition of the patient to potential complications should be attempted with a great all-out effort by all involved. 

A few comments about recurrent miscarriage rates. This is not unusual in patients with PCOS and may reflect many causes. It is helpful to achieve weight reduction and normalization of hormonal abnormalities (androgens, insulin, prolactin, thyroid function, etc.) prior to undergoing fertility treatment. A study demonstrating a reduction in miscarriage rates with the use of metformin must be substantiated by other investigators. This is a subject which will may be covered by others in this symposium.

Textbooks and major reviews do not often mention pelvic pains as a common symptom in women with PCOS. My general experience is that it is present in at least 1 of 5 women with this syndrome. It may not necessarily be associated with associated disease processes (see above), but represents ovarian discomfort and probable small follicle cyst ruptures. This occurs more dramatically in women prone to serous adenomas and recurrent large follicular serous cysts. Major bleeding may occur in rare instances in such patients, requiring instant attention and surgery. Suppressive therapy with OCs is indicated, and an experienced gynecologist should follow the progress of these patients with frequent examinations and ultrasonographic follow-ups.

In conclusion, treatments of the woman with PCOS are varied and tailored to each patient’s needs. The multiplicity of treatments available are but an indication of the lack of a uniform consensus of the treatment of this disorder. Hopefully, this summation and personal views may be helpful to some of you. I tend to be optimistic about the future, and truly hope that new agents will be employed that may reverse many of the features and potential complications of this syndrome and offer a happier and more productive life to all of you. I wish you health, and a life with less tribulations and one filled with happiness to you and your loved ones.