PCOS Treatment of Irregular Cycles: Progesterone Supplements

Poster by Amanda Kohn,www.implementingdesignism.org 

We've been talking about PCOS (Polycystic Ovarian Syndrome).

First we discussed its definition and symptoms, how it presents, its testing and diagnosis, and its possible causes.

Now we are discussing common treatment protocols for PCOS, and the pros and cons of each.

We've already discussed insulin-sensitizing medications like metformin, the TZDs, and inositol.

Then we discussed glucose-lowering medications for those who have developed overt diabetes.

Today, we start discussing treatments for regulating the menstrual cycle.

This mainly includes progesterone treatments and oral contraceptives for bringing on a period.

Today, we discuss progesterone treatments.

Disclaimer: I am not a medical health-care professional. While the following information is based on my best understanding of the research, always do your own research. This information is not a complete explanation of all the risks and benefits of a particular medication, nor is it medical advice about a health condition or treatment. Consult your healthcare provider before making any decisions about your care plan.

Trigger Warning: Passing mention of the possible weight effects of several medications, and passing mention of weight loss as the usual recommended treatment for menstrual irregularity.

Why It's Important to Treat for Menstrual Irregularity

Many women with PCOS experience irregular periods. It is probably the most common symptom of PCOS, and the one that brings the most attention to the syndrome in medical journals (along with infertility).

In a normal menstrual cycle, the lining of the uterus (endometrium) is exposed to various hormones produced by the body, especially estrogen. These hormones cause the lining to thicken and proliferate in anticipation of a possible pregnancy.

Once ovulation occurs, progesterone levels increase strongly in order to help sustain any pregnancy until the developing placenta can take over progesterone production. If pregnancy does not occur, a precipitous drop in progesterone levels will bring on the woman's period to flush out the unneeded extra lining.

Many women with PCOS have abnormally low levels of progesterone. They don't produce enough progesterone to bring on a period and flush out the uterine lining. This, plus egg follicles that don't develop properly, is why many women with PCOS have irregular periods. Some only skip a month now and again, while others may have only a few periods in a year. Still others may go years without a period.

Women with PCOS also tend to be estrogen-dominant, and as a result, the un-flushed uterine lining can be exposed to excessive levels of estrogen for prolonged periods. This can lead to abnormal overgrowth of the uterine lining (endometrial hyperplasia) and eventually, endometrial cancer.

Therefore, one of the most important treatment goals in PCOS is to regulate the menstrual cycle. There are two reasons that this is important:

• to improve ovulation for the purposes of fertility if children are desired
• to reduce the overgrowth of the endometrium and thereby reduce the chance for endometrial cancer later in life

The most common medication for regulating the menstrual cycle is the birth control pill, or The Pill. This ensures your body has a period every month. Most doctors see this as the treatment of choice for cycle regulation in PCOS.

However, if you've gone a long time without a period, many doctors will choose to use a progesterone medication first to "flush out" the uterine lining before trying other medications to regulate the cycle.

Although the focus of this series of posts is progesterone treatments and oral contraceptives, there are alternative treatments out there for regulating menstrual cycles. 

These will be covered in more detail in other posts, but can include lifestyle approaches (moderating carb intake, enhancing nutrition, and increasing exercise), acupuncture, herbs like vitex/chasteberry, the previously-discussed insulin-sensitizing medications like metformin or inositol, and perhaps vitamin D supplementation.

Care providers often also strongly promote weight loss for regulating menstrual cycles. This can be effective for some women but studies are often short-term and do not show what happens if weight loss is regained with time (as so often happens), nor do they acknowledge that weight loss can have risks as well as benefits (see the Weight References section of the blog). And while care providers make it sound like a sure thing, weight loss is not effective for regulating the periods in everyone; a number of women with PCOS still experience missed periods even after considerable weight loss. It is another tool that can be considered if you wish, but it's far from the magic bullet that doctors like to pretend it is.

Remember, there is no one "right" treatment protocol. Each woman must find the right combination of treatments that work best for her circumstances.

For some, this may include progesterone treatment to bring on a long-overdue period.

Progesterone Treatment for Menstrual Regularity 

Prometrium, image from Wikimedia

Progesterone supplements are usually used with a woman who hasn't had a menstrual cycle for quite a while. 

How long is too long? Some sources say at least 6 weeks between periods; others say at least six months between periods. The threshold at which progesterone supplements are prescribed will vary from provider to provider, but women should definitely not be going many months or even years between periods.

There are two main types of progesterone treatments for bringing on a period (withdrawal bleeding):

• Provera is the name of a synthetic type of progesterone (progestin) treatment; the generic name is medroxyprogesterone. This is the progesterone medication most often prescribed by care providers in the past. It is close to but not exactly like the progesterone produced in your own body
• Prometrium is the name of another progesterone supplement. It is synthesized from plants but is chemically identical to the progesterone made in your body. Some providers are moving to Prometrium more often these days, especially if pregnancy is desired, since Prometrium is safer to use in pregnancy than Provera

These medications have two main purposes for PCOS. They can be used for inducing a period in women who have not cycled on their own for a while and for managing ongoing abnormal uterine bleeding. In addition, they can be used to manage severe menopausal symptoms in older women.

In the interests of space, here we will only discuss their use for bringing on a period in women who have not cycled in a while.

Provera

Provera is a synthetic progestin which is similar but not quite identical to your body's own progesterone. Typically, Provera for inducing a period is prescribed as follows:

For the treatment of stopped menstrual periods (amenorrhea) and abnormal bleeding from the uterus, take this drug usually once daily for 5-10 days during the second half of the planned menstrual cycle or as directed by your doctor. Withdrawal bleeding usually occurs within 3-7 days after you stop taking the medication.

Provera comes in 2.5, 5.0, and 10 mg capsules. It's common to take a 5 mg or 10 mg capsule once a day for 5, 7, or 10 days (depending on your doctor's orders) in order to bring on the period. Other sources say to take Provera for 10 to 14 days every one to three months.

Provera works by simulating the high progesterone levels that occur near the end of your menstrual cycle, just before your period begins. It tricks your body into thinking that ovulation has occurred. Stopping the progesterone supplement simulates the drop in progesterone that occurs in a normal cycle when fertilization has not occurred, and should bring on your period within 2 weeks of stopping the medication. However, sometimes women do start their periods while still taking the Provera.

Some care providers only prescribe progesterone supplements periodically in women with PCOS. Others prefer to prescribe it regularly, about every few months, in order to promote a regular period and reduce the risk of endometrial hyperplasia. Discuss your situation with your care provider and decide what the best treatment routine is for you. 

If you are planning to try to become pregnant soon, you might want to reconsider whether or not to take Provera to bring on a period shortly before fertility treatment. Two recent studies found that taking Provera shortly before trying to conceive made the uterine lining more thin and women less likely to conceive. However, more research is needed to confirm this finding.

Side Effects and Risks of Provera

Side effects of Provera can be considerable, although short-term use for inducing a period is less risky than long-term use for menopause symptoms. The most common short-term symptoms include:

• dizziness
• headache 
• abdominal pain and cramping
• breast tenderness

Longer-term symptoms can include:

• breasts that are tender or produce a liquid
• changes in menstrual flow
• irregular vaginal bleeding or spotting
• acne
• growth of hair on face
• loss of hair on scalp
• difficulty falling asleep or staying asleep
• drowsiness
• upset stomach
• weight gain or loss

More uncommon (but serious) symptoms include:

• pain, swelling, warmth, redness, or tenderness in one leg only
• slow or difficult speech
• dizziness or faintness
• weakness or numbness of an arm or leg
• shortness of breath
• coughing up blood
• sudden sharp or crushing chest pain
• fast or pounding heartbeat
• sudden vision changes or loss of vision
• double vision
• blurred vision
• bulging eyes
• missed periods
• depression
• yellowing of the skin or eyes
• fever
• hives
• skin rash
• itching
• difficulty breathing or swallowing
• swelling of the hands, feet, ankles, or lower legs
• increased blood pressure

Although not always listed as a possible side effect, many women report that they have experienced extreme irritability and mood swings while on progestin medications. This is one of the most distressing side effects for many women.

Some lab animals which were given medroxyprogesterone developed breast tumors, but it is not clear whether this translates to development of breast cancer in humans. Medroxyprogesterone may also increase the chance of blood clots that move to the lungs (pulmonary embolism) or brain (stroke). Again, these risks are more related to long-term use than short-term use, but it's still important to be aware of the possibility.

Contraindications to Provera include prior history of breast, ovarian, or uterine cancer; blood clots; stroke; seizures; migraines; depression; unexplained vaginal bleeding; incomplete miscarriage; asthma; high blood pressure; diabetes; or heart, kidney, or liver disease.

Provera may create negative drug interactions with St. John's Wort, Rifampin, 

aminoglutethimide (Cytadren), certain anti-seizure medications, and other meds. If you are on any drugs (or any herbs), be sure to discuss that with your care provider before taking Provera.

Prometrium

Some care providers promote the use of bio-identical progesterones like Prometrium instead of synthetic progestins. They believe it will more closely mimic the body's natural process and result in better outcomes.

In some research, about 80% of women who took Prometrium (oral micronized progesterone) were able to re-start their periods.

Anecdotally, some women with PCOS report that they have had better results with Prometrium. Many report less moodiness, less dizziness, and fewer PMS-like symptoms. However, while many people have fewer side effects with Prometrium, others have had more. You have to test out which version is better for your body.

Prometrium is taken for the same reasons as Provera. It tricks the body into thinking it has ovulated; withdrawing the Prometrium will cause a drop in progesterone, hopefully triggering the woman's period within about 2 weeks. However, Prometrium is not as potent as Provera, so it needs a much higher dosage.

For bringing on a period, some sources recommend 100-300 mg of Prometrium for the last 10-12 days of what should be a 28-day cycle. Other sources suggest 400-600 mg per day.

For women who experience very strong estrogen dominance and wild fluctuations of symptoms when going on and off progesterone, some care providers recommend a low continuous dose of Prometrium, rather than constantly going on and off the progesterone.

Prometrium is available as an oral capsule, and can also be used as a vaginal suppository. There is a similar form available as an injectable intramuscular progesterone, or as a vaginal gel (Crinone). There may be fewer side effects with the vaginal versions but it can be a bit messy. The oral form might be best taken at bedtime because it can cause significant drowsiness in many women.

One major disadvantage of Prometrium is that it is much more expensive. Provera is available in a generic form so it can be much more affordable.

Provera should not be used if a woman might conceive a pregnancy. It has mild androgenic effects and can negatively affect a developing male fetus. In contrast, Prometrium is often prescribed by care providers to help lessen the risk for miscarriage in early pregnancy (more on that below).

Side Effects and Risks of Prometrium

Prometrium has many of the same side effects as Provera; re-read the above list to review these side effects. It is especially important to watch for possible signs of blood clots or allergic reaction.

The progesterone in Prometrium is micronized and suspended in a peanut oil solution to make it more bioavailable; the injectable form of intramuscular progesterone is suspended in sesame oil. People with peanut allergies need to avoid Prometrium and people with sesame allergies need to avoid intramuscular progesterone.

Although most women have fewer side effects with Prometrium, some women report more, especially dizziness, drowsiness, headache, acne or bloating/fluid retention. Weight gain is not uncommon with prolonged use of any progesterone supplement, but most non-menopausal women with PCOS will not take it long enough to experience this.

Some sources report that ketoconazole, an anti-fungal medication sometimes used for hair loss with PCOS, inhibits the absorption of Prometrium in the liver and therefore may potentiate its effects. However, oral ketoconazole is rarely prescribed these days as the FDA has recently warned of its potential for liver toxicity and adrenal damage. Furthermore, this warning does not extend to ketoconazole shampoo, which is the form used most often with hair loss concerns. It is unclear at this time whether the mere use of the shampoo would potentiate the effects of Prometrium. Discuss this possibility with your provider.

Controversy Over Use in Pregnancy

One big controversy these days is whether or not Prometrium should be given to women in early pregnancy to try and prevent miscarriage. Many providers are quite comfortable with doing this, while others contend it is not beneficial and may carry risks.

Why would Prometrium be given in pregnancy? Progesterone is important is sustaining a pregnancy, and women with PCOS tend to have low progesterone levels and higher miscarriage rates. The hope is that by supplementing progesterone, the risk for miscarriage will be lessened in this group.

In a woman without PCOS, the corpus luteum (the remains of the egg follicle on the ovary) produces progesterone for the pregnancy until the placenta is developed enough to take over progesterone production. Because follicular development tends to be weaker in women with PCOS, they may not produce enough progesterone to sustain a pregnancy. Supplementing progesterone is thought to help lessen the chance for miscarriage. Prometrium is the only viable choice for this because Provera is contraindicated in pregnancy.

However, using progesterone supplements in pregnancy is somewhat controversial. Many care providers do not believe that progesterone supplements are necessary or helpful for preventing miscarriage and will not prescribe them at all. Others regularly prescribe Prometrium for women with PCOS, especially if there is a history of miscarriage. Many providers also prescribe it for women who have gone through In Vitro Fertilization treatments, or for those experiencing threatened miscarriage.

Anecdotally, many women with PCOS who experienced repeated miscarriages report that progesterone supplements helped them to finally carry a pregnancy to term. Therefore there is fierce support for this practice on some PCOS boards.

However, progesterone supplements during pregnancy have occasionally been associated with hypospadias, an abnormal placement of the hole at the end of the penis in male babies. Rare complications have included cases of cleft lip, cleft palate, and cardiac issues. Whether this is true for all progesterone supplements, however, is not clear. Although some Prometrium-related websites caution against its use in pregnancy, it may actually only be the synthetic progesterones like Provera that carry this added risk. Some doctors' websites state outright that natural progesterone does not carry any additional risk, while others state that there may be a small increased risk. If in doubt, discuss this with your provider.

Prometrium is considered a Category B medication in pregnancy. The safest rating is a Category A. Category B means that animal studies have shown no increased risks to the fetus, but that there haven't been enough tests in humans to confirm this lack of harm. Given the natural reluctance of researchers to experiment on pregnant women, this rating is unlikely to change soon, but most providers seem to consider Prometrium a relatively safe drug for early pregnancy.

A 2013 Cochrane Collaboration review of the use of progesterones for preventing miscarriage found no evidence for its routine use in preventing miscarriages. However, in the subgroup of women with a history of repeated miscarriage, progesterones strongly lowered the risk for miscarriage and did not increase the risk for adverse outcomes like birth defects.

Another Cochrane review noted that progesterone supplements strongly lowered the rate of miscarriage in women experiencing threatened miscarriages. Both reviews noted that the research trials were of relatively poor quality and that more research is needed to guide clinicians on this topic.

So the bottom line so far appears to be that progesterone supplements should not be used routinely in all women in order to prevent miscarriage, but that there is probably a role for it under certain conditions, such as a threatened miscarriage or in women with a strong history of recurrent miscarriages.

Whether or not it should be used routinely in women with PCOS and no other risk factors has not been studied adequately. It may behoove women with PCOS to ask their providers to track their progesterone levels early in pregnancy and consider prescribing a natural progesterone if their levels appear low.

One other potential benefit of vaginal progesterone in pregnancy is that some research suggests that it may lower the rate of spontaneous pre-term birth in women with a shortened cervix in the second trimester.

Since the pregnancies of women with PCOS tend to be at increased risk for cervical insufficiency and pre-term birth, it is interesting to speculate whether low progesterone levels may be part of this risk, and whether or not early supplementation with Prometrium or vaginal progesterone may help prevent some cases of preterm birth in this group. However, at this time, this possibility remains speculative.

Summary

It is very important that women have regular periods so that the uterine lining does not build up and become cancerous over time.

There are many approaches that can help regulate the menstrual cycle in women with PCOS. For many, just taking metformin is enough to make periods more regular. For some, a lifestyle approach can make periods more regular. Alternative approaches that some find helpful include acupuncture or herbs like vitex (vitex often helps bring the body's hormones into balance and improves progesterone levels). There are also natural progesterone creams that contain much lower levels of progesterone than the medications discussed here and which may be useful for women with only mild progesterone deficiencies.

But some women with PCOS do not cycle even with these approaches. For these women, an oral contraceptive may be needed to have regular periods and prevent endometrial overgrowth. More on that in our next post.

However, if it has been more than a few months since you've had a period, care providers usually want to flush out the endometrium before beginning other treatments. The most common way to do this is to prescribe progesterone to bring on a period. Provera (a synthetic progestin) is the most commonly prescribed form, but Prometrium (a bio-identical progesterone) is gaining favor among many providers because side effects are often less severe.

Bringing on a long-overdue period with progesterone is not an easy process, and many women report significant bloating, cramps, and mood swings, as well as an extremely heavy period afterwards. This can be truly miserable for some women.

Because it can be such a difficult process, some women with PCOS avoid treatment with progesterones, preferring simply to avoid the bother of a period altogether. However, this will increase their long-term risk for endometrial cancer. As tough as it is to endure a long-overdue period, it is important to do so for your long-term health.

Once the endometrial lining has been flushed out, then other approaches to regulating the menstrual cycle can be tried. Lifestyle approaches, herbs, acupuncture and insulin-sensitizing medications can all help address the underlying hormonal imbalances that cause periods to be irregular. If all else fails, an oral contraceptive (The Pill) can be used, although many women with PCOS prefer to avoid this if possible.

Bottom line, women with PCOS need to prevent endometrial hyperplasia by some means or other. What method is best will depend on your individual circumstances and responsiveness, but progesterone can sometimes be part of that treatment strategy.

In addition, bio-identical progesterone may also hold promise for preventing some cases of miscarriage, and perhaps also for preventing some cases of preterm birth, although more study is needed.

Although they certainly carry risks and should not be over-utilized, progesterone supplements definitely have a role to play in treating some aspects of PCOS. 

References

Books About PCOS

• http://verity-pcos.org.uk/guide_to_pcos/pcos_books/general_pcos - Verity's guide to books on PCOS; a more varied list than many organizations have

PCOS Information 

• http://www.uptodate.com/contents/polycystic-ovary-syndrome-pcos-beyond-the-basics
• http://www.hormonehelpny.com/column/pcos.htm

General Information about Progesterone for Regulating Cycles

• http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682470.html - information about medroxyprogesterone (Provera) for regulating menstrual cycles
• - information about Prometrium for regulating menstrual cycles
• http://www.womenlivingnaturally.com/articlepage.php?id=106 - information about bioidentical progesterone for regulating cycles (instead of synthetic progestins)
• http://www.soulcysters.net/showthread.php/9789-Provera-vs-Prometrium - anecdotal experiences of Provera vs. Prometrium in women with PCOS
• http://www.project-aware.org/Resource/articlearchives/differences.shtml - information about the differences between natural and synthetic progesterones, written by a pharmacist

Studies on Provera and PCOS

Obstet Gynecol. 2012 May;119(5):902-8. doi: 10.1097/AOG.0b013e31824da35c. Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. Diamond MP, Kruger M, Santoro N, Zhang H, Casson P, Schlaff W, Coutifaris C, Brzyski R, Christman G, Carr BR, McGovern PG, Cataldo NA, Steinkampf MP,Gosman GG, Nestler JE, Carson S, Myers EE, Eisenberg E, Legro RS; Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network. PMID: 22525900

OBJECTIVE: To estimate whether progestin-induced endometrial shedding, before ovulation induction with clomiphene citrate, metformin, or a combination of both, affects ovulation, conception, and live birth rates in women with polycystic ovary syndrome (PCOS). METHODS: A secondary analysis of the data from 626 women with PCOS from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network trial was performed. Women had been randomized to up to six cycles of clomiphene citrate alone, metformin alone, or clomiphene citrate plus metformin. Women were assessed for occurrence of ovulation, conception, and live birth in relation to prior bleeding episodes (after either ovulation or exogenous progestin-induced withdrawal bleed). RESULTS: Although ovulation rates were higher in cycles preceded by spontaneous endometrial shedding than after anovulatory cycles (with or without prior progestin withdrawal), both conception and live birth rates were significantly higher after anovulatory cycles without progestin-induced withdrawal bleeding (live births per cycle: spontaneous menses 2.2%; anovulatory with progestin withdrawal 1.6%; anovulatory without progestin withdrawal 5.3%; P<.001). The difference was more marked when rate was calculated per ovulation (live births per ovulation: spontaneous menses 3.0%; anovulatory withprogestin withdrawal 5.4%; anovulatory without progestin withdrawal 19.7%; P<.001). CONCLUSION: Conception and live birth rates are lower in women with PCOS after a spontaneous menses or progestin-induced withdrawal bleeding as compared with anovulatory cycles without progestin withdrawal. The common clinical practice of inducing endometrial shedding with progestin before ovarian stimulation may have an adverse effect on rates of conception and live birth in anovulatory women with PCOS.

Int J Clin Exp Pathol. 2013 May 15;6(6):1157-63. Print 2013. Does progesterone-induced endometrial withdrawal bleed before ovulation induction have negative effects on IUI outcomes in patients with polycystic ovary syndrome? Dong X, Zheng Y, Liao X, Xiong T, Zhang H. PMID: 23696936

...The present study was performed to investigate whether progesterone-induced endometrial bleed before ovulation induction affects pregnancy in patients with PCOS who underwent intrauterine insemination (IUI) treatment. A total of 241 IUI cycles were retrospectively analyzed. Patients enrolled in this study underwent ovulation induction with IUI treatment from Jan. 2011 to Dec. 2012. The study group consisted of 184 cycles with progesterone-withdrawal bleed before ovulation induction. The control group included 57 cycles with spontaneous menses. The clinical characteristics, ovulation induction parameters and IUI outcomes, such as pregnancy rate and live birth/ongoing pregnancy rate, were compared between the two groups...In conclusion, our study showed that progesterone exerted a negative effect on endometrial development, which seemed to be associated with reduced pregnancy results in ovulation induction with IUI cycles.

 Prometrium Studies

Fertil Steril. 1991 Dec;56(6):1040-7. Factors associated with withdrawal bleeding after administration of oral micronized progesterone in women with secondary amenorrhea. Shangold MM, Tomai TP, Cook JD, Jacobs SL, Zinaman MJ, Chin SY, Simon JA. PMID: 1743319

OBJECTIVE: To compare two dosages of oral micronized progesterone (P) and placebo for withdrawal bleeding and side effects. DESIGN: Prospective, randomized, double-blind... INTERVENTIONS: A 10-day course of (1) oral micronized P 300 mg, (2) oral micronized P 200 mg, or (3) placebo...RESULTS: Withdrawal bleeding occurred in 90% of women taking 300 mg, 58% of women taking 200 mg, and 29% of women taking placebo (P less than 0.0002 for 300 mg versus placebo). Side effects occurred similarly among the groups (P = not significant). Lipid concentrations were unchanged. Endogenous E2 and treatment P concentrations were of limited predictive value for withdrawal bleeding. CONCLUSIONS: Progesterone 300 mg induced significantly more withdrawal bleeding than placebo, with similar side effects...