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Understanding PCOS, the Hidden Epidemic by Jeffrey Dach, M.D.
 
    

PCOS Polycystic Ovary Syndrome -
Anovulatory Androgen Excess

by Jeffrey Dach MD 
Seventeen year old Alice has PCOS (Polycystic Ovary Syndrome).  Alice came with her Mom into the office and told me her story.  Alice has been overweight, borderline diabetic, and has facial hair and acne caused by elevated testosterone.  At age 12, Alice started normal menstrual cycles, but her cycles began fluctuating and periods stopped at age 15.  Her gyne doctor diagnosed PCOS (Polycystic Ovary Syndrome), and put her on birth control pills to regulate her cycles. The birth control pills caused adverse side effects of weight gain weight and elevated blood pressure (hypertension), so she stopped them. 

Progesterone is the Most Logical Form of Treatment and Actually Works

Two months ago, Alice was switched over from the birth control pills to natural progesterone, taking a 100 mg capsule twice a day for 14 days on, 14 days off. The progesterone was successful, restoring a normal menstrual period, and a return to regular cycles.

BCP’s (birth control pills) are usually prescribed by the ob-gyne doctor to regulate cycles in the PCOS patient. This standard treatment is not the best one.  There is a better more logical alternative that actually works called natural progesterone. Both John R Lee MD, and JeriLynn Prior MD advocate the use of natural progesterone as a far better alternative to birth control pills.  After all, birth control pills (BCP's) are a chemical form of castration, and work by inhibiting ovulation.

This article will explain the cause of PCOS, and will describe the signs and symptoms of PCOS, including the clinical features of PCOS, and give you a simple questionnaire to determine if you have PCOS. This article will also explain why natural progesterone is the best treatment, and a much better choice compared to birth control pills.

PCOS was Rare When First Described in 1935, Now Quite Common.

When PCOS (polycystic ovary syndrome) was first described in 1935 by Stein and Leventhal, it was fairly rare.(55) Nowadays, it is quite common, involving 6 to 10 per cent of the female population, affecting 3.5 to 5 million women. (24) Why the increased incidence?  Some believe that endocrine disruptor chemicals in the environment are to blame.(60A)

Obese Young Lady with PCOSClinical Signs and Symptoms Of PCOS
 

Oligomenorrhea or amenorrhea (no periods), Anovulation (no ovulation)
Weight gain, obesity, Hirsutism (excessive hair growth, male pattern)
Insulin resistance (pre-diabetes), Acne, Male-pattern baldness, Multiple small ovarian cysts on sonogram, Acanthosis Nigrans (darkening of the skin at the nape of the neck and under arms)-indicator of hyperinsulinemia

Above Left Image: Obese Young Lady with PCOS, anovulatory infertility, acne and facial hair.

A Brief Moment for Definitions:

Hirsutism PCOS Polycystic Ovary SyndromeDefinition of ovulation: This is the when an egg pops out of the follicle in the ovary, and starts on the long trip down the fallopian tube to the uterine cavity where it can be fertilized to form a new baby. Ovulation causes high progesterone production by corpus luteum in the ovary. Menstrual Cycles are regular.

Definition of Anovulation: The egg doesn't’t pop out and there is no progesterone production. The cycles are irregular or absent.

Above Left Image: Typical hirsutism, with hair growth under the chin.


Bearded Fat Lady at the Circus, She Had PCOSHow Do You Know If You Have PCOS?

This is the PCOS Questionnaire.(
63)(64) and these are the Links to questionnaire articles: 

1) PCOS Questionnaire  

2) PCOS questionnaire

If you answer Yes to 2 out of 3 of the following questions, this indicates high likelihood (80%) of PCOS.

Above Left Image: The bearded fat lady at the circus. She had PCOS.

Length of Menstrual Cycle, Variable Length

1) Between the ages of 16 and 40, was length of your menstrual cycle (on average) greater than 35 days and/or totally variable ?

Hair Growth (Male Pattern)

2) During your menstruating years (not including during pregnancy), did you have dark, coarse hair on your three or more of these sites? Upper lip? chin? breasts? chest between the breasts? back? belly? upper arms? upper thighs?

Obesity

3)
Were you ever obese or overweight between the ages of 16 and 40?



Hormone Levels during the Menstrual Cycle with normal ovulation.
The green dotted line is progesterone which rises days 14-22. 
The progesterone is absent in PCOS, because there is no ovulation,  
and the green line stays flat on the chart, instead of rising


What Causes PCOS ?

The world’s greatest authority, Leon Speroff MD, says: “A question which has puzzled gynecologists and endocrinologists for many years is what causes polycystic ovaries. There is an answer which is appealing in its logic and clinical applicability. The characteristic polycystic ovary emerges when a state of anovulation persists for any length of time”
(1Clinical Gynecologic Endocrinology and Infertility by Leon Speroff MD p.493

PCOS is the end result of not ovulating, (no progesterone production) for a long time (a few years), resulting in a vicious cycle which self perpetuates anovulation, causing increased testosterone production by the ovary. Insulin resistant diabetes and obesity aggravate the problem.  As you might expect, PCOS is a major cause of infertility. 

About 10% of patients thought to have PCOS actually have an underlying genetic enzyme defect in adrenal steroid synthesis called Non-Classical CAH. This can be diagnosed with a Cortrosyn stimulation test, and a 21-OH genetic test called CAHDtex from Esoterix.  If present, treatment is successful with low dose adrenal steroid tablets (cortef, dexamethasone, prednisone) which restores fertility and reverses the acne. (see below discussion on non-classical CAH).

Oral Contraceptives for PCOS (BCP's)

Birth control pills are a chemical form of castration, which prevent ovulation. Lack of ovulation is the primary defect in PCOS, so birth control pills merely perpetuate the primary defect. Birth control pills can restore regular bleeding periods, however, this is artificial, and aggravate the underlying PCOS problem rather than solve it. In addition, birth control pills are known to worsen insulin resistance and diabetes. (2)

"PCOS may affect between 3.5 and 5.0 million young women in the United States, it arguably may be the most important general health issue affecting young women. BCP's (OCPs) are the traditional therapy for the chronic treatment of PCOS…… limited evidence raises the issue that BCP's (OCPs) may aggravate insulin resistance and exert other untoward metabolic actions that possibly enhance the long-term risk for diabetes and heart disease."



JeriLynn Prior MD Says:

“The fundamental problem with PCOS is not making progesterone for two weeks every cycle. This lack of progesterone leads to an imbalance in the ovary, causes the stimulation of higher male hormones and leads to the irregular periods and trouble getting pregnant. Progesterone is usually missing—replacing it therefore makes sense. “



John R Lee MD says:

"I recommend supplementation of normal physiologic doses of progesterone to treat PCOS. If progesterone levels rise each month during the luteal phase of the cycle, as they are supposed to do, this maintains the normal synchronal pattern each month, and PCOS rarely, if ever, occurs. Natural progesterone should be the basis of PCOS treatment, along with attention to stress, exercise, and nutrition.

If you have PCOS, you can use 15 to 20 mg of progesterone cream daily from day 14 to day 28 of your cycle. If you have a longer or a shorter cycle, adjust accordingly. The disappearance of facial hair and acne are usually obvious signs that hormones are becoming balanced, but to see these results, you'll need to give the treatment at least six months, in conjunction with proper diet and exercise."  This is quoted from the The John R Lee Medical Letter 1999.(10)

Self-Medication Not Recommended

Some young women find out about progesterone on internet messenger boards, and then proceed on their own to buy it over-the-counter.  The progesterone cream may successfully restores cycles in many cases.  However, self - medication is not recommended.  It is best to work with a knowledgeable physician.  If you have PCOS and need a doctor to prescribe progesterone, you can find a knowledgeable physician on the ACAM or A4M doctor's directory.(65)(66)  Always work closely with a knowledgeable physician.


Can PCOS be Treated with Natural Progesterone? 

YES 
by Dr. Jerilynn Prior (3)

"Progesterone talks back to the hypothalamic and pituitary (brain) hormones that control the ovaries and stops them from stimulating the ovaries to make too much testosterone."

Dr Prior recognizes that the (BCP) pill, with its synthetic type of progesterone, does help women with PCOS to a certain degree. 

But her goal for PCOS patients is, "to return the brain/ovary system to a normal balance. The goal of the BCP Pill is the opposite - it must suppress the brain-ovary system to prevent pregnancy."

To help her PCOS patients achieve a normal hormonal balance, she prescribes oral micronized progesterone (trade name Prometrium) which is a bio-identical hormone. Taking this natural progesterone for two weeks every month (called cyclic progesterone therapy) may help the brain to develop the normal cyclic rhythm that is missing in PCOS.

Interestingly, Dr. Prior believes there is another benefit of cyclic progesterone therapy. She explains, "most doctors don't realize progesterone antagonizes and inhibits the enzyme (called 5-alpha reductase) that is needed to make testosterone into dihydrotestosterone. Dihydrotestosterone is the powerful male hormone that talks hair follicles into making coarse hair and too much oil that causes acne."
Above quote is attributed to Jerilyn Prior MD Web Site.(3)

PCOS Ultrasound showing ovarian cystsUltrasound of PCOSWHAT MAKES YOUR OVARIES TICK Insights about Ovulation, Fertility, PCOS and more. (4)

Click Herer for an Interview with Jerilynn C. Prior, M.D. posted on the Virgina Hopkins Health Watch. Dr. Jerilynn Prior is a professor of endocrinology at the University of British Columbia. She is a pioneer in research involving women's menstrual cycles, ovulation, progesterone and bone loss. 

Above Left Image: Polycystic ovary on ultrasound image.

Interview Quoted from Virgina Hopkins Health Watch:

JLML: How do you track your luteal phase with a basal temperature chart?

JCPrior: If you record your oral temperature every morning for an entire month using a digital thermometer, record the temperature in the evening before you go to bed, and record any illness or early or late rising, you can quantitatively determine which days of the cycle are high progesterone days. You can then take all of those daily temperatures from the beginning of one period until the day before the beginning of the next, and do an average of the temperatures. The point where your temperature goes above that average, and stays above it, is the beginning of the luteal phase. It will go back down when your period starts or just before. That's how easy it is to figure out your luteal phase length! That alone is valuable information for women who are having miscarriages that may be due to a short luteal phase.

JLML: I have found that women who are more aware of their cycles are often better able to self-treat for hormone imbalances.

JLML: What else can you tell us about anovulatory cycles? The other kind of ovulation disturbance I called “turned on.” The woman experiencing this kind of ovulation disturbance will complain of weight gain, acne, and hair where she doesn’t want it. The biology of this is less clear, but it relates to insulin excess and insulin resistance, which have effects both on the brain by increasing LH (luteinizing hormone) levels, and directly on the ovary. Excess insulin sits on receptors on the theca cells, the outer coat of the ovary, and makes them more responsive to the hormonal environment, and therefore they make more androgens [testosterone, male hormones].

JLML: Aha! So that's why a high sugar diet aggravates polycystic ovary syndrome. The excess sugar creates high insulin levels, which stimulate androgen production in the ovary, which suppresses ovulation.

JCPrior: The higher LH and the higher androgen levels set up a signal that inhibits the follicle from ovulating. Because each follicle grows and creates a lake of fluid around it, if it doesn’t burst and release its egg, a cyst is left. Therefore you get into a situation of high or normal estrogen levels, high androgens, and low progesterone. That condition is usually characterized by obesity, especially middle-of-the-body obesity, androgen signs such acne, oily skin, facial and breast hair, and head hair loss. Because estrogen tends to be higher with weight gain, these are the women who have a higher breast cancer and endometrial cancer risk. They may also have the worst PMS symptoms.

JLML: So this is yet another good reason to avoid sugar and refined carbohydrates such as white bread and pasta.

JCPrior: And it's another good reason to get plenty of aerobic or endurance-type exercise, which is one of the best ways of getting the insulin levels down and decreasing PMS. With turned on ovulation disturbances you need to correct three problems: The first is to bring progesterone into balance –and for this you use physiologic doses of progesterone. Next, you often you need to block the effect of the male hormone. There's a medicine called spironolactone which I use that blocks androgen action at the cell level. Finally, if a person has a family history of diabetes or is quite obese, then I may use a drug called metformin (Glucophage) that sensitizes the body to insulin and allows the insulin levels to go down.
 
JLML: I have found that supplemental progesterone, a good amount of exercise, and a low sugar diet, low simple carbohydrate and low fat diet with plenty of vegetables will often restore balance.
The above interview posted courtesy of Virginia Hopkins Health Watch. (4)
 

Help for PCOS - Cyclic Progesterone Therapy

by Dr. Jerilynn C. Prior and Celeste Wincapaw (5

Jerilynn C. Prior MD Says:

I use cyclic progesterone therapy as the heart of treatment for PCOS- anovulatory androgen excess.(6)  Progesterone is the hormone made by the ovary after an egg is released.

The fundamental problem with PCOS is not making progesterone for two weeks every cycle. This lack of progesterone leads to an imbalance in the ovary, causes the stimulation of higher male hormones and leads to the irregular periods and trouble getting pregnant. Progesterone is usually missing—replacing it therefore makes sense. Progesterone talks back to the hypothalamic and pituitary (brain) hormones that control the ovary, and stops them from stimulating the ovary to make too much testosterone.

Taking progesterone for two weeks every month (called cyclic progesterone) may help the brain to develop the normal cyclic rhythm that is missing in PCOS. Progesterone also counterbalances the steadily high estrogen levels that the PCOS ovary produces even if you have no periods. Progesterone will prevent estrogen over-stimulation of the uterine lining (endometrial hyperplasia) and heavy flow. It may also interfere with the action of high estrogen on the breasts, therefore preventing tenderness and “lumpiness” and perhaps even the risk for breast cancer.

Finally, and most doctors don’t realize this, progesterone antagonizes and inhibits the enzyme (called 5-alpha reductase) that is needed to make testosterone into dihydrotestosterone. Dihydrotestosterone is the powerful male hormone that talks hair follicles into making coarse hair and too much oil that causes acne.

Useful Tools for Patients:

Protocol for Cyclic PROGESTERONE THERAPY patient handout sheet (6)
 
Menstrual cycle diary log sheet patient handout (7
 
______________________________________________

Guidelines for Progesterone Cream Dosage for PCOS (8)

Early PCOS - 32mg from day 12-26

Advanced PCOS - 54mg from day 12-26 of your cycle

Severe PCOS with pain, 64mg of progesterone cream from day 5-26 , to address pain from endometriosis. Then try to wean back to a lesser dose or to extend breaks to fall into line with a day 12-26 cycle. Note, if you are using a regime day 5-26 in the first 4-7 months until symptoms settle, please be aware you are using a program suggested to enhance fertility. (8)

_______________________________________________

Dr. Lam Progesterone Guidelines for Polycystic Ovary Syndrome (9)

Dr. Lam follows Dr John R Lee pioneering use of progesterone.

Apply 20 mg of progesterone cream during day 14 to 28 of the menstrual cycle. Adjust accordingly if for longer or shorter cycle. As the hormonal balance is regained, facial hair and acne, two commonly associated symptoms, will disappear. (9)

_______________________________________________

Other treatable causes of anovulation

1) Low thyroid function (hypothyroid) causes menstrual irregularity, anovulation and infertility.  Ovulation and fertility is restored by thyroid medication.  Ovarian cysts also resolve.

2) Vitamin D deficiency is associated with anovulation.  Resolves with Vitamin D.

3) Iodine deficiency causes ovarian cysts and anovulation, reversed by iodine supplementation.

________________________________________________

Other Useful Drug Treatments for PCOS:

Issue                                            Drug Treatment

Infertility, anovulation:     Clomid clomephine, induces ovulation.
Insulin Resistance:           Metformin improves insulin sensitivity.(39)(39A)
Acne, Facial Hair:            Spironlactone, Aldactone inhibits testosterone.
________________________________________________
PCOS—polycystic ovary syndrome.

Standard diagnostic assessments:


1) History may show: Variable or anovulatory menstrual pattern, obesity, hirsutism, and the absence of breast discharge.

2) Pelvic sonogram may show: 10 or more cysts in each ovary, 'string of pearls'.
The ovaries are generally 1.5 to 3 times larger than normal.

3) Labs may show:
Elevated DHEAs and free testosterone.
Ratio of LH to FSH is greater than 1:1, as tested on Day 3 of the menstrual cycle.
The pattern is not very specific and was present in less than 50% in one study.

Common assessments for associated conditions or risks.

1) Fasting biochemical screen and lipid profile
2) 2-hour oral glucose tolerance test (GTT) in patients with risk factors (obesity, family history, history of gestational diabetes) and may indicate impaired glucose tolerance (insulin resistance) in 15-30% of women with PCOS. Frank diabetes can be seen in 65–68% of women with this condition. Insulin resistance can be observed in both normal weight and overweight patients.

Lab tests for exclusion of other disorders that may cause similar symptoms:

1) Prolactin
2) TSH
3) 17-hydroxyprogesterone to rule out 21-hydroxylase deficiency (CAH).
4) Fasting insulin level or GTT with insulin levels (also called IGTT).
5) Fasting Glucose to Fasting Insulin ratio <4.5 is cheaper method 

ICD-9 Codes: PCOS ICD-9 256.4  Amenorrhea ICD-9 626.0

___________________________________________


Non Classical CAH Congenital Adrenal Hyperplasia, also known as Non-Classical 21 Hydroxylase Deficiency (NC21OHD)

Non-Classical CAH or 21 Hydroxylase Deficiency is the most common genetic disease known, occurring in 1% of New Yorkers, and up to 3% in ethnic groups such as of Ashkenazi Jews, Hispanics, Italians, and Yugoslavs.(68

Ten per cent of patients with PCOS actually have Non-Classical CAH. The  underlying genetic defect causes an enzyme deficiency in the adrenal gland which reduces the ability of the adrenal to make cortisol.  Instead of making cortisol, the adrenal steroid pathways are shunted towards testosterone causing elevated testosterone and the typical symptoms of hair growth (hirsutism), and acne and there may also be menstrual irregularities, anovulation, and infertility.(69)(70)

What is the 21 Hydroxylase Enzyme?

This is a key enzyme in the adrenal gland which converts cholesterol into cortisol.  In the Classical form of CAH, the 21 hydroxylase enzyme (21-OH) is severely deficient with resulting low cortisol levels.  In the Non-Classical form however, the 21 hydroxylase (21-OH) enzyme is still working fairy well with only a slight reduction in activity, and cortisol levels are usually normal, while testosterone levels may be elevated to a variable degree.  The Human Adrenal Steroid synthesis pathways and the adrenal enzymes involved can be understood on this chart from Quest Labs.(71)

How to Make the Diagnosis of Non-Classical CAH? Cortrosyn Stimulation

The most definitive diagnosis is done with a Cortrosyn Stimulation test (0.25 mg) which measures  17-hydroxyprogesterone (17-OHP) at 0 and 60 minutes after SQ injection of the Cortrosyn (ACTH).

This test in simple terms is described here:

First a preliminary (baseline ) blood test is done for various hormones including 17-OH, this is followed by a subcutaneous injection of 0.25 mg of a drug called Cortrosyn which is a form of ACTH which stimulates the adrenal glands to make more hormones. An hour (60 minutes) after the Cortrosyn injection, a post stimulation blood sample is drawn for lab testing for 17-OH and other hormones.

Patients with Non Classic 21-OH Deficiency typically show 60-min stimulated 17-OHP values between 1,500 and 10,000 ng/dl.  This chart shows how the 17-OHP values cluster at three areas for normal (below 1,500), Non-Classical CAH (1500-10,000) and, and Classical CAH (above 10,000). (72) The Quest Lab testing algorithm is shown here.(73)

Genetic  Testing for 21-OH Deficiency

Genetic testing is now available and very useful.  This test shows whether or not there is a mutation in the CYP21A2 gene coding for the 21-Hydroxylase Enzyme.(74) The CAHDtex test by Esoterix is useful in showing the exact mutation in the CYP21A2 gene. (75) Once the exact mutation in the CYP21A2 gene is known, refer to this chart to determine the severity of the enzyme defect.(76)  Genetic testing of other family members is usually recommended once a sibling is found with the mutation.
 
Clinical Presentation in Children

In children, the signs include premature onset of puberty, cystic acne, accelerated growth, and advanced bone age. Premature development of pubic hair may occur as early as 6 months of age (due to elevated testosterone). The severe cystic acne may be unresponsive to oral antibiotics and retinoic acid (Accutane).
 
Although the child may be taller than the other kids in early childhood, this early growth spurt finishes early (because of epiphyseal fusion), and final height ends up shorter than usual. Thus, these kids are tall children but short adults.

Another feature may be male pattern baldness in a female involving the top of the head and sparing the sides.

Teenagers and Young Adults - Major Cause of Infertility

Teenage girls may present with features of elevated testosterone such as facial hair (hirsutism), acne and menstrual irregularities or anovulation. Young adult females may present with the chief complaint of infertility. It has been generally recognized that infertility of undetermined cause in women may be reversed with glucocorticoid (cortef or prednisone) therapy, which most likely treats an occult Non-Classical CAH Syndrome.  William Mc Jefferies MD successfully treated thousands of such cases ( The Safe Uses of Cortisol).(77)

Treatment of Non Classical CAH with Cortisol Restores Fertility

Oral tablets containing low dose cortisol sucessfully treat Non-Classical CAH and reverse the symptoms restoring fertility.  The cortisol suppresses ACTH and reduces the testosterone production by the adrenal.

Dr. Maria New has followed a large group of 400 patients with Non-Classical CAH, and she treats them with 0.25 mg dexamethasone at the hour of sleep, and she notes it takes about 3 months for reversal of acne and infertility.  Hirsutism takes longer to respond, about 30 months.

The cost for a dexamethasone tablet is $0.50, and the 3-month treatment cost is estimated to be $45. Compare this $45 dollars to the infertility treatment cost of $30,000 for one cycle of in vitro fertilization . Dr. Maria New says that many patients presenting with infertility actually have NonClassical CAH, and fertility could be restored easily with treatment with oral cortisol tablets such as cortef, dexamethasone, or prednisone. (69)  Before you spend a fortune on in-vitro fertilization for infertility, it would be prudent to rule out Non-Classical CAH with a simple genetic test. For more information on CAH, see my article on this topic: A Commonly Missed Cause of Infertility, NonClassical CAH by Jeffrey Dach MD (78)
 
Jeffrey Dach MD
7450 Griffin Rd Suite 180/190
Davie, FL 33314

Phone: 954-792-4663
Email: drdach@drdach.com
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Link to this article:
http://jeffreydach.com/2008/02/13/understanding-pcos-the-hidden-epidemic-by-jeffrey-dach-md.aspx

REFERENCES

(1) http://www.amazon.com/Clinical-Gynecologic-Endocrinology-Infertility-Editorial/dp/0781747953
The Clinical Gynecologic Endocrinology and Infertility: Leon Speroff MD

(2) http://jcem.endojournals.org/cgi/content/full/88/5/1927
A Modern Medical Quandary: Polycystic Ovary Syndrome, Insulin Resistance, and Oral Contraceptive Pills, The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 5 1927-1932

(3) http://www.pcosupport.org/newsletter/articles/article122707-3.php
Can PCOS be Treated with Natural Progesterone? Jerilynn Prior, PCOSA Today Newsletter

(64) http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1949220
Can Fam Physician. 2007 June; 53(6): 1041–1047.  Polycystic ovary syndrome. Validated questionnaire for use in diagnosis, Sue D. Pedersen, et al.

(65)http://www.acamnet.org/site/c.ltJWJ4MPIwE/b.2242497/k.2C78/Integrative_Medicine_
Physicians/apps/kb/cs/contactsearch.asp

ACAM doctor's directory

(66) http://www.worldhealth.net/pages/directory
A4M doctor's directory

(67) http://jeffreydach.com/2008/02/27/a-commonly-missed-cause-of-infertility-nonclassical-cah-by-jeffrey-dach-md.aspx A Commonly Missed Cause of Infertility, NonClassical CAH by Jeffrey Dach MD
 

Non Classical Adrenal Hyperplasia CAH 21-OH Deficiency

(68) http://jcem.endojournals.org/cgi/content-nw/full/91/11/4205/F8
FIG. 8. Non-classical CAH 21 Hydroxylase Deficiency Chart of Disease frequencies in different ethnic groups.

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