Tuesday, September 29, 2015

PCOS Treatment: Anti-Androgen Medications

September is Polycystic Ovarian Syndrome (PCOS) Awareness Month. PCOS is a condition that affects many people of size, yet it is often under-diagnosed and under-treated. It's important to bring more awareness to this condition and its treatment choices, so every year I post something about a particular aspect of PCOS.

Here are some of the previous entries in our periodic continuing series on PCOS:
Now we are discussing common treatment protocols for PCOS (and the pros and cons of each) ─ from a size-friendly point of view (meaning no diet talk or weight loss promotion). We've already discussed:
Today, we discuss anti-androgenic medications, especially their use for common PCOS symptoms like hirsutism (excess facial and body hair), alopecia (hair loss), or acne.

Disclaimer: I am not a health-care professional. This information is not a complete explanation of all the risks and benefits of a particular medication, nor is it medical advice. Always do your own research and consult your healthcare provider before making decisions about your care.

Trigger Warning: Passing mention of the possible weight effects of several medications.

Anti-Androgen Medications

 Since one of the major issues in PCOS is androgen excess, one of the major goals of treating it is to reduce the levels of androgens (male hormones) in the blood ─ or at least to reduce its effects.

As we have seen in previous posts, some birth control pills can have a major anti-androgenic effect and lessen many PCOS symptoms, which is why they are the most commonly prescribed medication for PCOS. However, there are some drawbacks.

Not all oral contraceptives have an anti-androgenic effect, and some significantly worsen androgens. Combined oral contraceptives also increase the risk for blood clots, particularly the anti-androgenic ones, and may have lower birth control efficacy in high-BMI women. Some argue that they merely put a band-aid on symptoms while not adequately addressing the underlying causes of PCOS issues.

Thus while birth control pills can be one option for PCOS, it's important to have other options as well. One of these choices can be an anti-androgen. These medications either prevent the body from making as many androgens, or they limit the activities and effects of androgens. Treatment with anti-androgenic medications may help:
  • Lower androgen levels
  • Reduce hirsutism
  • Reduce acne 
  • Minimize hair loss issues
While anti-androgens can reduce some PCOS symptoms, it's vitally important to know that they can also cause birth defects and must be taken with an extremely reliable form of birth control, even in women with fertility issues. 

Occasional spontaneous ovulation does happen even in those struggling with infertility, and the chance of birth defects is high in women who take anti-androgen medications. As a result, anti-androgens are often taken with oral contraceptives in order to make sure pregnancy is prevented. Sometimes the combination works even better than alone, giving it an added bonus.

As with insulin-sensitizing medications, anti-androgens are not FDA-approved for the treatment of PCOS. Research reviews note the poor quality of research on these drugs, so the best anti-androgen for treating PCOS symptoms is not yet known, nor is the best combination of anti-androgen and oral contraceptive. Women who want to use any of these drugs should be extremely cautious and discuss all pros and cons thoroughly with their health care provider.

Finally, it is important to note that it takes a long trial of treatment (6-18 months) before it is clear whether a particular anti-androgen drug is impacting your symptoms. Because the hair growth cycle is long, improvement is generally slow and gradual. You must be patient before you decide whether or not an anti-androgen drug is helping.

And remember, the drug's benefits last only as long as you are taking the drug, and the risk of side effects with some drugs is substantial. If the drug's benefits are only modest, some people may feel they are not worth the long-term risk of side effects.

Most Common Anti-Androgen Medications

There are a number of choices of anti-androgen medications for PCOS. These include:
  • Spironolactone (brand name: Aldactone)
  • Flutamide (brand name: Drogenil or Eulexin)
  • Finasteride (brand name: Propecia or Proscar)
  • Bicalutamide (Brand name: Casodex, Calutide)
  • Certain combination oral contraceptives
  • Drosperinone
  • Cyproterone Acetate (CPA; brand names: Androcur and Cyprostat)
  • Insulin-Sensitizing Medications
Let's look at each of these a bit more in detail.

Spironolactone (brand name: Aldactone)

 Spironolactone is the most common anti-androgen drug used for women with PCOS. It is a potassium-sparing diuretic, usually prescribed for treating edema (excess fluid) or high blood pressure. It is also an aldosterone antogonist. Its use for PCOS symptoms is off-label but has been going on for years.

Spironolactone is thought to help in the following way:
Spironolactone inhibits the testosterone secreted by the body, and also competes for hormone receptors in the hair follicles. Receptors are sites on cells which allow hormones or chemical to bind to them, creating a reaction. If another chemical is in the receptor site, androgens cannot bind to them and stimulate the reaction causing hair growth.
Spironolactone has been shown to significantly lessen facial hirsutism in women with PCOS. A recent Cochrane meta-analysis suggests that 100 mg daily is quite effective against hirsutism, although it noted that the quality of this evidence was low and more research is needed. Other OB guidelines have suggested that higher doses may be needed in some women, but that it's best to build dosage up slowly over time.

Some recent research also suggests that spironolactone might also help women with hair loss, either with or without accompanying minoxidil (Rogaine). Some women report that it slows down hair loss, but most do not report that it restores hair that has been lost. Although it does not seem particularly effective against alopecia, it is another option that can be tried since responsiveness varies between patients.

Its use for acne, however, is even less clear. A 2009 meta-analysis notes that studies on its use for acne are scarce and very small. More research is needed.

For many women with significant hirsutism, spironolactone is the medication of choice. However, again, spironolactone can cause significant birth defects, so it must always be used with a form of extremely reliable birth control in women who have even the smallest chance of becoming pregnant. This usually means the Pill, since oral contraceptives are one of the most effective forms of birth control. Since some types of the Pill can also help with hirsutism, the combination of the Pill and spironolactone can be particularly effective for many women with PCOS. However, not all find it effective.

Because spironolactone is a diuretic, you will need to be monitored to make sure you don't build up too much potassium in the blood. Nausea, fatigue, headache, lightheadedness, indigestion, thirst, and excessive urination are common side effects; heart arrhythmias can occur if potassium levels spike. Liver enzymes must be monitored regularly for signs of hepatotoxicity.

You can read more about the uses, side effects, and cautions for spironolactone here and here. Guidelines for its use with acne are discussed here.

Flutamide (brand name: Drogenil or formerly Eulexin)

 Another medication that works similarly to spironolactone is flutamide. From one website:
Flutamide is a non-steroidal antiandrogen that is devoid of other hormonal activity. It most likely acts after converting to 2-hydroxyflutamide, which is a potent competitive inhibitor of dihydrotestosterone (DHT) binding to the androgen receptor.
A few studies have found that flutamide helps restore regular menstrual cycles and ovulation in women with PCOS, but it is most useful against hirsutism. It is available in the United States, but is usually prescribed for men with prostate cancer, not women with PCOS. As a result, most of the hirsutism research on it is European.

Flutamide can have significant liver toxicity, so some organizations recommend against it use. Flutamide can also result in significant gastrointestinal upset, as well as issues with dry skin. Because of these side effects, flutamide is generally considered unsuitable for the treatment of acne and other skin problems where its benefit is only minimal.

Because it is more effective for hirsutism, the benefit/risk ratio for this is more controversial. A recent Cochrane meta-analysis suggests that flutamide (250 mg, twice daily) is "effective and safe" against hirsutism, although it noted that the quality of this evidence was low. Another recent meta-analysis disagreed, stating:
Due to its risk for hepatotoxicity, flutamide is not considered a first-line therapy. If used, the lowest effective dose should be administered with careful monitoring of liver enzymes.
Flutamide may be somewhat effective for slowing down the progress of alopecia (hair loss). It likely does not restore thinned hair but may slow down or stop the process from continuing. Again, more research is needed.

Some care providers feel that flutamide is relatively safe with careful monitoring. Close monitoring of liver function via regular blood tests is very important. The chance for birth defects is quite high with Flutamide, so again, a very reliable form of birth control must be used, or it may be prescribed only for women with no childbearing potential.

You can read more about Flutamide here, here, and here.

Finasteride (brand name: Propecia or Proscar)

Finasteride is a 5 alpha-reductase inhibitor. It is FDA-approved for the treatment of baldness and/or Benign Prostatic Hyperplasia (BPH) in men. It has a relatively good safety profile and is well tolerated by most men, but it is quite expensive. It is not approved for use with PCOS or with women.

Finasteride has been shown in some research to be effective against hirsutism, though not for hair loss in women. It works by preventing the androgens from getting into the cells. However, the recent Cochrane meta-analysis notes that the research on finasteride is inconsistent and therefore conclusions cannot be reached. It does not appear to be effective against hair loss in women.

Finasteride can cause headaches and depression. It is associated with a very high risk of birth defects (pregnancy drug category X), so it is not used in women who have even the smallest chance of becoming pregnant. Some doctors consider it an option, however, for women who have no childbearing potential anymore.

You can read more about finasteride here.

Bicalutamide (brand name: Casodex, Calutide)

 A fairly new anti-androgen option is bicalutamide. It is a 5 alpha-reductase inhibitor, like finasteride. Its mechanism of action is as follows:
Bicalutamide acts as a pure antiandrogen by binding to the androgen receptor and preventing its activation and subsequent upregulation of androgen-responsive genes by androgenic hormones. In addition, bicalutamide accelerates the degradation of the androgen receptor.
Although it can impact liver function, bicalutamide is considered to be less likely to cause damage than some other anti-androgen drugs, which is a big advantage.

Like finasteride, it is associated with a high risk of birth defects and is contraindicated in women with any chance of becoming pregnant. However, there is some minimal research on its use in women.

You can read more about bicalutamide here.

Combination Oral Contraceptives

As we have discussed before, certain combination oral contraceptives (using both estrogen and progestin) have strong anti-androgen effects. As a result, they are often the first-line treatment for PCOS and for hirsutism in general.

One OB website sums up the mechanism of action:
Oral contraceptives...suppress pituitary production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn suppress ovarian androgen production. OCs also may reduce adrenal androgen production, although the mechanism of action is unclear. 
The estrogen component in OCs increases hepatic production of sex hormone-binding globulin (SHBG), thereby decreasing free testosterone levels. The progestin component antagonizes 5α-reductase and the androgen receptor; it also may increase hepatic metabolism of testosterone and can increase SHBG when the OC has low androgenic activity.
However, the strength of anti-androgenic effect in oral contraceptives varies. Some birth control pills (second generation, especially those involving levonorgestrel) have strong androgenic effects, which can make symptoms worse in some women with PCOS.

Many of the later oral contraceptives (third- and fourth-generation) have a stronger anti-androgenic effect. These can be used on their own or in combination with other anti-androgenic drugs (usually spironolactone) to treat hirsutism and acne.

Unfortunately, the oral contraceptives with the strongest anti-androgenic effects tend to have the strongest risk of blood clots, particularly for women of size and/or women with PCOS. Each woman's unique medical history and risk factors must be considered very carefully before use of these oral contraceptives. You can read more about these risks here, here, and here.

Here are further details of two of the most commonly-prescribed anti-androgenic oral contraceptives, those using droperinone and those using cyproterone acetate.

Drosperinone

 Drosperinone (also known as 1,2-dihydrospirorenone) is a synthetic steroidal progestin which has weak anti-androgenic properties. Structurally, it is similar to spironolactone.

When combined with ethinyl estradiol, it becomes the combination birth control pill called Yasmin, sometimes called a "fourth-generation" oral contraceptive. It has a modest effect against hirsutism and acne. (In a slightly different formulation, drosperinone plus estradiol is called Angeliq, and is sometimes used for menopausal symptoms.)

Yasmin is contraindicated in people with a history of liver, kidney, or adrenal insufficiency. Potassium levels must be carefully monitored in anyone on this medication.

Some research suggests that the risk for blood clots is significantly increased in people on Yasmin, both compared to those not on any birth control pills at all, and in those on other types of birth control pills. Certain risk factors (obesity, high blood pressure, family history of blood clots, diabetes, etc.) may raise the risk even more. Still, doctors point out that the absolute risk remains relatively low, and certainly lower than the risk of blood clots during pregnancy.

Cyproterone Acetate (CPA; brand names: Androcur and Cyprostat, among others)

 CPA is another progestin that has anti-androgenic properties and may be used alone or as part of certain birth control pills. It inhibits production of androgens in ovarian theca cells, and also competes with androgens at receptor sites.

 From its Wikipedia entry:
Cyproterone Acetate...is a synthetic steroidal antiandrogen drug with additional progestogen and antigonadotropic properties. Its primary action is to suppress the activity of the androgen hormones such as testosterone and its more potent metabolite dihydrotestosterone (DHT) in the body, effects which it mediates via competitive antagonism of the androgen receptor and inhibition of enzymes in the androgen biosynthesis pathway.
CPA is most often used as an anti-androgen treatment for men with prostate cancer. In PCOS women, it is an effective treatment for significant hirsutism and acne. It may be even more effective for this when combined with metformin. 

 CPA may also slow the rate of hair loss in women with alopecia but this is not as well-researched. On the other hand, there are a number of anecdotal stories of women who say their hair loss greatly increased after stopping oral contraceptives with CPA. The true influence of CPA on alopecia remains to be figured out.

 In the U.K. and Canada, CPA has been combined into the oral contraceptives known as Dianette and Diane-35. CPA and the Diane birth control pills are not available in the U.S.

The amount of CPA in most birth control pills is fairly small, and has only a modest effect on hirsutism. Higher doses of CPA tend to have more impact on hirsutism. However, it takes quite a while for the CPA in birth control pills to affect hirsutism; a trial of at least 6 months is needed, and often the maximum effect is not attained until 2-3 years later.

CPA can have significant liver toxicity. Liver enzymes, cortisol and electrolyte levels must be monitored when on CPA. A woman's ability to absorb vitamin B12 may also be impaired, while iron-binding abilities may be enhanced. B12 and ferritin levels should be monitored when on this medication long-term.

Nausea, vomiting, headache, depression, weight changes, edema, increased blood pressure, gallstones, and skin spots are potential side effects. Again, birth defects can occur with this drug, so effective birth control is needed, which is why it is usually administered in oral contraceptive form.

Blood clots are also a significant risk; women on birth control pills with CPA have a higher risk for blood clots than women on certain other types of the Pill, but some OB organizations feel that they can be worth the risk. Like Yasmin, the absolute risk of a blood clot is fairly low, but may be increased in women with certain risk factors.

If you consider use of CPA, a CPA oral contraceptive (like Dianette), or a drosperinone oral contraceptive (Yasmin), be sure to consult with your care providers carefully about your health history, risk factors, and the benefit/risk ratio of these medications. 

You can read more about Dianette oral contraceptives here and the newer oral contraceptives in general here.

Insulin-Sensitizing Medications

Insulin-sensitizing drugs are not anti-androgen drugs per se. However, by reducing insulin levels, they may have some anti-androgenic effects and can be somewhat effective against hirsutism or acne. Since they have the distinct advantage of being effective against multiple PCOS symptoms at the same time, some providers will prescribe insulin sensitizers first in women with PCOS.

Metformin (brand name Glucophage) is the most commonly used insulin-sensitizing medication in PCOS. TZDs like Actos and Avandia may be somewhat effective against hirsutism but because of concerns over their safety, are not used as commonly as metformin. You can read more about TZDs here.

Metformin has been shown in some past research to be as good as or somewhat better than oral contraceptives alone in reducing hirsutism in women with PCOS. A 2009 literature review for the American Academy of Family Physicians notes that past research showed that metformin was as effective for treatment of hirsutism as many oral contraceptives, although later research did not confirm its effectiveness.

Nowadays, metformin and other insulin-sensitizers are not considered to be first-line drugs for use alone against hirsutism. One recent review said:
Monotherapy with an insulin sensitizer does not significantly improve hirsutism. While insulin sensitizers improve important metabolic and endocrine aberrations in polycystic ovary syndrome, they are not recommended when hirsutism is the sole indication for use.
More recent research suggests that metformin modestly increases the effectiveness of other anti-hirsutism medications, particularly oral contraceptives and spironolactone. In other words, while metformin probably shouldn't be prescribed by itself for hirsutism, it may well be prescribed in combination with an anti-androgen medication (probably spironolactone) or an oral contraceptive.

Herbs for Anti-Androgenic Effects

In addition to traditional medicines, there are herbs that are reputed to have anti-androgenic effects.  

For example, herbal spearmint tea has long been used as an anti-hirsutism treatment in Middle Eastern cultures. Research suggests that spearmint tea may have mild anti-androgenic effects and may be helpful with hirsutism, but longer studies are needed to evaluate this.

Other possible herbal agents may include red reishi (a mushroom used in Chinese medicine), licorice root, Chinese peony, green tea, black cohosh, and saw palmetto extract. Many women with PCOS use chaste tree/vitex in particular. More information on the (rather sparse) research behind these possibilities can be found here.
Conclusion

 Some of the most distressing symptoms of PCOS are the ones that affect a woman's appearance. Most (though not all) women with PCOS experience excess facial and body hair. Many experience cystic acne, and some also experience thinning hair on the head. Add in the obesity common to PCOS, and symptoms strike right at the heart of a woman's self-esteem.

Although most clinicians focus more on menstrual cycle and insulin resistance, the majority of women with PCOS actually seek treatment for cosmetic issues or fertility concerns. Distressing cosmetic issues are often the biggest priority because of the impact on social lives and self-esteem.

Most clinicians utilize oral contraceptives as the first-line treatment for symptoms of androgen excess like hirsutism. If there is not enough improvement after about 6 months, they may add in an insulin-sensitizing medication or an anti-androgen drug as well. Patients are often counseled to consider cosmetic solutions as well (such as electrolysis, laser treatment, or eflornithine for hirsutism).

Anti-androgen drugs have been shown to be reasonably effective against hirsutism and acne, but are not very effective in slowing down hair loss and usually do not restore hair that is already gone. CPA may show some promise for alopecia but more research is needed, and it is also not uniformly available. It also carries significant risks for blood clots, and withdrawal from the medication may make hair loss worse.

The efficacy of anti-androgen medications varies strongly from person to person. Some women get very effective help from these drugs, while others get little relief at all.

Some only get results when combining anti-androgen drugs with birth control pills and/or metformin. Others get better relief from herbs, or a combination of herbs and cosmetic treatments. Still others never get much effect at all, whatever the combination of treatments. As always, the key is to experiment with various treatment protocols and see what works for you.

Again, because the risk for blood clots, birth defects, and toxicity with these anti-androgen drugs is very high, be sure you thoroughly research the pros and cons of each choice, consult carefully with a healthcare provider about your risk factors, get baseline and follow-up blood tests, and have a foolproof plan for birth control in place.

Anti-androgen drugs can be an effective tool in the PCOS toolbox. Some women find them very helpful, while others prefer to avoid them. They do carry significant risks so consider all the pros and cons thoroughly before you decide on whether to make them part of your PCOS toolbox.


References

 Anti-Androgen Medications, General Information
Spironolactone 

Cochrane Database Syst Rev. 2009 Apr 15;(2):CD000194. doi: 10.1002/14651858.CD000194.pub2. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Brown J1, Farquhar C, Lee O, Toomath R, Jepson RG. PMID: 19370553
AUTHORS' CONCLUSIONS: From the studies included in this review, there is some evidence to show that spironolactone is an effective treatment to decrease the degree of hirsutism but there was no evidence for effectiveness for the treatment of acne vulgaris. Studies in this area are scarce and small. Individual study data indicates some superiority of spironolactone over other drugs but results cannot be generalised.
J Endocrinol Invest. 2005 Jan;28(1):49-53. Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity and lipid profile. Zulian E et al.  PMID: 15816371
...Twenty-five patients...were studied at baseline and then received oral spironolactone (100 mg/die) for 12 months...The efficacy of spironolactone on the androgenic clinical aspects of PCOS has been confirmed in this study. Furthermore, our data show that long-term treatment with spironolactone exerts no negative effects on lipoprotein profile and glucose metabolism; more relevant beneficial effects on glucose and lipid metabolism were observed when the antiandrogen was associated with weight loss in overweight PCOS women.
Dermatol Clin. 2010 Jul;28(3):611-8. doi: 10.1016/j.det.2010.03.011. Innovative use of spironolactone as an antiandrogen in the treatment of female pattern hair loss. Rathnayake D1, Sinclair R. PMID: 20510769
...Although androgens play a key role in the pathogenesis of male pattern hair loss (MPHL), the role of androgens in female pattern hair loss (FPHL) is less well established. Satisfactory treatment response to antiandrogen therapy supports the involvement of androgens in the pathogenesis of FPHL...Spironolactone both reduces adrenal androgen production and exerts competitive blockade on androgen receptors in target tissues. Spironolactone has been used off-label in FPHL for over 20 years. It has been shown to arrest hair loss progression with a long-term safety profile. A significant percentage of women also achieve partial hair regrowth....
Flutamide

Arch Gynecol Obstet. 2009 Mar;279(3):321-7. doi: 10.1007/s00404-008-0719-z. Epub 2008 Jul 8. The risk of hepatotoxicity during long-term and low-dose flutamide treatment in hirsutism. Dikensoy E1, Balat O, Pence S, Akcali C, Cicek H. PMID: 18607612
OBJECTIVE: Flutamide is an effective drug in treatment of hirsutism. Hepatotoxicity occasionally may occur with therapeutic doses (750-1500 mg/day), 3 months after initiation of treatment. Monitoring of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels is recommended to obviate serious hepatotoxicity. MATERIALS AND METHODS: Two hundred and fourteen patients with mean age of 20.9+/-2.34 years suffering from hirsutism were included in the study...Fifty-seven patients with PCOS (group 1) were given flutamide 125 mg/day + oral contraceptive. Sixty patients with PCOS (group 2) were given flutamide 250 mg/day + oral contraceptive. Forty-seven patients with IH (group 3) were given flutamide 125 mg/day alone, and 50 patients with IH (group 4) were given flutamide 250 mg alone. Thirty women in control group (group 5) were given placebo only...RESULTS: No incidence of increase in AST or ALT levels (>or= 45 U/L) was observed in any of the groups...CONCLUSION: We conclude that flutamide in a dosage of 125 or 250 mg daily is a safe drug in the long-term treatment of hirsutism. The follow-up of patients receiving flutamide can be done by monitoring AST or ALT levels for hepatotoxicity.
Ginekol Pol. 2013 Apr;84(4):258-62. Clinical efficacy of low dose flutamide plus Diane-35 in the treatment of idiopathic hirsutism and polycystic ovary syndrome. Boztosun A1, Açmaz G, Ozturk A, Müderris II. PMID: 23700857
...26 polycystic ovary syndrome and 24 idiopathic hirsutism patients were evaluated...All patients received 125 mg Flutamide once a day and Diane 35 tablets for 21 days of each month, for 12 months...The decreases in Ferriman-Gallwey scores were significant in both groups in the 6th and 12th month of therapy. Combined treatment significantly decreased total and free testosterone, DHEAS and significantly increased SHBG levels in both groups and additionally decreased levels of LH, androstenodione and LH/FSH ratio in the polycystic ovary syndrome group. CONCLUSION: Combined treatment was effective and safe in the treatment of hirsutism. Combined regimens have additional effects on the treatment of hirsutism.
Finasteride

Gynecol Endocrinol. 2003 Feb;17(1):57-63. The benefits of finasteride for hirsute women with polycystic ovary syndrome or idiopathichirsutism. Lakryc EM, et al.  PMID: 12724020
...The aim of this study was to evaluate the clinical and hormonal effects of finasteride on hirsute women with idiopathic hirsutism or polycystic ovary syndrome. Twenty-four women were randomly divided into two groups: those given placebo and those given finasteride 5 mg/day. The treatment period was 6 months. All patients were evaluated before the beginning of treatment (baseline) and after 3 and 6 months of treatment...All the patients treated with finasteride perceived a reduction in hirsutism after 6 months. In conclusion, our data suggest that finasteride may be effective for the treatment of the hirsute woman with idiopathic hirsutism or polycystic ovary syndrome.
Bicalutamide

 Gynecol Endocrinol. 2002 Feb;16(1):63-6. New alternative treatment in hirsutism: bicalutamide 25 mg/day. Müderris II1, Bayram F, Ozçelik B, Güven M. PMID: 11915584
The efficacy of low-dose bicalutamide (25 mg/day) in the treatment of hirsutism was investigated in this study...42 women with hirsutism...received 25 mg/day bicalutamide... Clinical improvement in the degree of hirsutism was observed in all patients by the same author. The modified Ferriman-Gallwey scores decreased from a mean of 22.0 +/- 5.1 to 8.6 +/- 3.5 (p < 0.0001). The reduction in hirsutism scores was 41.2 +/- 11.4% at 3 months and 61.6 +/- 11.1% at 6 months. In conclusion, bicalutamide at 25 mg/day is an effective drug in the treatment of patients with hirsutism.
Comparisons of Different Anti-Androgen Medications

Cochrane Database Syst Rev. 2015 Apr 28;4:CD010334. doi: 10.1002/14651858.CD010334.pub2.
Interventions for hirsutism (excluding laser and photoepilation therapy alone). van Zuuren EJ1, Fedorowicz Z, Carter B, Pandis N. PMID: 25918921
...AUTHORS' CONCLUSIONS: Treatments may need to incorporate pharmacological therapies, cosmetic procedures, and psychological support. For mild hirsutism there is evidence of limited quality that OCPs are effective. Flutamide 250 mg twice daily and spironolactone 100 mg daily appeared to be effective and safe, albeit the evidence was low to very low quality. Finasteride 5 mg daily showed inconsistent results in different comparisons, therefore no firm conclusions can be made. As the side effects of antiandrogens and finasteride are well known, these should be accounted for in any clinical decision-making. There was low quality evidence that metformin was ineffective for hirsutism and although GnRH analogues showed inconsistent results in reducing hirsutism they do have significant side effects. Further research should consist of well-designed, rigorously reported, head-to-head trials examining OCPs combined with antiandrogens or 5α-reductase inhibitor against OCP monotherapy, as well as the different antiandrogens and 5α-reductase inhibitors against each other....
Beigi A, Sobhi A, Zarrinkoub F. Finasteride versus cyproterone acetate-estrogen regimens in the treatment of hirsutism. International Journal of Gynaecology and Obstetrics. 2004; 87: 29-33. PMID: 15464773
...Forty hirsute women were enrolled in a prospective randomized trial. Twenty-nine had polycystic ovary syndrome (PCOS) and 11 had idiopathic hirsutism. Patients were randomly treated with finasteride (5 mg/day; n=20) or CPA plus EE2 [CPA (25 mg/day on days 5-14) plus EE2 (20 microg/day on days 5-25) n=20] for 9 months... CONCLUSION: Finasteride and CPA plus EE2 are equally effective in decreasing hirsutism, despite significantly different effects on serum hormone levels.
Calaf J, Lopez E, Millet A, et al. Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel clinical trial. Journal of Clinical Endocrinology and Metabolism. 2007; 92: 3446-3452. PMID: 17566093
OBJECTIVE: Our objective was to test the efficacy and tolerability of three doses of flutamide (125, 250, and 375 mg) combined with a triphasic oral contraceptive (ethynylestradiol/levonorgestrel) during 12 months to treat moderate to severe hirsutism in patients with polycystic ovary syndrome or idiopathic hirsutism. DESIGN: We conducted a randomized, double-blind, placebo-controlled, parallel clinical trial...A total of 119 patients were included in the intention-to-treat analysis... CONCLUSIONS: Flutamide at 125 mg daily during 12 months was the minimum effective dose to diminish hirsutism in patients with polycystic ovary syndrome or with idiopathic hirsutism.
Moghetti P, Tosi F, Tosti A, et al. Comparison of spironolactone, flutamide and finasteride efficacy in the treatment of hirsutism: a randomized, double blind, placebo-controlled trial. Journal of Clinical Endocrinology and Metabolism. 2000; 85: 89-94. PMID: 10634370
To compare objectively the efficacies of spironolactone (100 mg/day), flutamide (250 mg/day), and finasteride (5 mg/day) in the treatment of hirsutism, 40 hirsute women were randomly assigned to double blind treatments with 1 of these 3 drugs or placebo for 6 months...spironolactone, flutamide, and finasteride are all effective in the treatment of hirsutism. After a 6-month course of therapy, the clinical efficacies of these drugs, at least at the doses used, are similar.
Anti-Androgen Effects of Various Oral Contraceptives 

Fertil Steril. 2012 Jul 13. Comparative study of the therapeutic effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone in patients with polycystic ovary syndrome. Bhattacharya SM, Jha A.  PMID: 22795636
OBJECTIVE: To compare the effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone, in polycystic ovary syndrome (PCOS), after 6 and 12 months of therapy. DESIGN: Double-blind randomized controlled trial... PATIENT(S): Women (n = 171) with PCOS (Androgen Excess Society criteria, 2006). INTERVENTION(S): The three-arm trial involved 58, 56, and 57 cases in desogestrel, cyproterone acetate, and drospirenone groups, respectively... CONCLUSION(S): No difference in effects after 6 months. At 12 months, cyproterone acetate showed the strongest antiandrogen activities. Effects on metabolic parameters were identical. 
Arch Gynecol Obstet. 2014 Aug;290(2):321-8. doi: 10.1007/s00404-014-3217-5. Epub 2014 Mar 28. Comparison of two oral contraceptive forms containing cyproterone acetate and drospirenone in the treatment of patients with polycystic ovary syndrome: a randomized clinical trial. Kahraman K1, Sükür YE, Atabekoğlu CS, Ateş C, Taşkın S, Cetinkaya SE, Tolunay HE, Ozmen B, Sönmezer M, Berker B. PMID: 24676694
PURPOSE: To compare the effects of combined oral contraceptives (OCs) containing cyproterone acetate and drospirenone in the treatment of polycystic ovary syndrome (PCOS). METHODS: Fifty-two patients with PCOS were randomized in two groups: group A (n = 26) received 0.035 mg ethinyl estradiol + 2 mg cyproterone acetate and group B (n = 26) received 0.03 mg ethinyl estradiol + 3 mg drospirenone-containing OCs for 12 months...CONCLUSIONS: Cyproterone acetate containing OCs seem to be more effective to treat clinical hirsutism in patients with PCOS after 12 months of treatment.
Drosperinone

Ther Clin Risk Manag. 2008 Apr;4(2):487-92. Use of ethinyl estradiol/drospirenone combination in patients with the polycystic ovary syndrome. Mathur R, Levin O, Azziz R.   PMID: 18728832   Free full text available here.
...One of the main issues in COC [combined oral contraceptive] therapy is choosing the most appropriate progestin component to provide the greatest anti androgenic effects. Drospirenone, a relatively new progestin, has shown benefit in the PCOS population when used in conjunction with ethinyl estradiol. We now review the role of COCs in PCOS, focusing specifically on drospirenone. Controversy over metabolic effects of COCs in PCOS is also discussed. 
Cyproterone Acetate (CPA) 

See Mathur 2008 above for CPA information also
Gynecol Endocrinol. 2008 Oct;24(10):590-600. The effects of Diane-35 and metformin in treatment of polycystic ovary syndrome: an updated systematic review. Jing Z, et al. PMID: 19012104
...A systematic review and meta-analysis were conducted. Randomized controlled studies applying Diane-35 and metformin for treating PCOS were included. The primary outcome was hirsutism...CONCLUSIONS: Diane-35 is superior to metformin in reducing androgens, but inferior to metformin in reducing insulin. Whether Diane-35 deteriorates lipid metabolism and insulin resistance is still unclear.
Treatment of Hirsutism
General Review of PCOS Treatments

Clin Evid (Online). 2009 Jan 15;2009. pii: 1408. PCOS. Cahill D. PMID: 19445767  Free full text available here.
...CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: finasteride, flutamide, metformin, spironolactone, cyproterone acetate-ethinylestradiol (co-cyprindiol), interventions to achieve weight loss, ketoconazole, and mechanical hair removal.
Am Fam Physician. 2009 Apr 15;79(8):671-676. Drug Treatment for Polycystic Ovary Syndrome. Radosh, L. American Academy of Family Physicians. Free full text available here. 
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