Polycystic Ovary Syndrome -...

Stephen R Hammes, M.D., Ph.D.

Division of Endocrinology and Metabolism

University of Rochester Medical Center

Polycystic Ovary Syndrome: Are Androgens

all Bad in Women?

Stein-Leventhal Description of PCOS

Stein I.F. and Leventhal M.L. (1935) American Journal of Obstetrics and Gynecology 29, 181-191.

Outline

1. Definition of PCOS

2. Pathophysiology of PCOS

3. Treatment of PCOS

4. Are androgens all bad??

Some Basic Facts and Statistics about PCOS

1. The incidence of PCOS is 5 - 10% of reproductive age women.

2. PCOS is one of the leading cause of infertility in women.

3. PCOS is often associated with obesity and metabolic syndrome;

thus, as the obesity epidemic rages on, so does PCOS.

4. About 50% of women with PCOS also have insulin resistance.

This number increases as the population becomes more obese.

1. Hyperandrogenemia - either with laboratory values or with

Symptoms (e.g., hirsutism, acne, balding, voice deepening)

2. Oligomenorrhea - periods less frequent than every 35 days

or 10 per year

3. Exclusion of related disorders

Definition of PCOS

1990 NIH Consensus Conference

1. Oligo- or anovulation

2. Clinical or biochemical signs of hyperandrogenemia

3. Polycystic ovaries

Definition of PCOS

Rotterdam Criteria (2003)

In addition to excluding other causes, two of the following are needed:

>12 follicles of 2-9 mm diameter

and/or an ovarian volume >10cm3

PCOS Ultrasounds

Ways to Measure Testosterone

Total Testosterone

2% Free 98% Protein Bound

80% SHBG (tight)20% Albumin (loose)

Bioavailable

Testosterone

Ways to Measure Testosterone

Total Testosterone

2% Free 98% Protein Bound

80% SHBG (tight)20% Albumin (loose)

Bioavailable

Testosterone

What we use:

1. Free and total testosterone by LC-MS/MS

2. SHBG

3. Calculate BAT: www.issam.ch/freetesto.htm

The definition of PCOS is a moving target, but most

agree that one needs to have:

1. Biochemical or clinical Hyperandrogenemia

2. Oligo/Anovulation

What is the Pathophysiology of PCOS?

Hormone Levels During the Menstrual Cycle

Follicular Phase Luteal Phase

Ovulation

Estrogen

Progesterone

14 280Day:

Oocyte

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Hypothalamic/Pituitary/Gonadal Axis

Oocyte

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

GnRH is Secreted from the Hypothalamus in

a pulsatile Fashion

Oocyte

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

GnRH First Stimulates FSH Secretion

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

FSH Promotes Follicle Growth

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

FSH Increases Aromatase Activity; thus

Increasing Estradiol Secretion

EstradiolFSH

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

EstradiolFSH

Estradiol Acutely Increases GnRH Secretion

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

GnRH (+)

Inhibin (-)

Increased Pulsatile GnRH Secretion Favors

LH over FSH Release

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

OVULATION

(Oocyte and

Corpus Luteum)

The LH Surge Triggers Ovulation

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Progesterone is Secreted from the Ovary

and the Corpus Luteum

Progesterone

OVULATION

(oocyte and

Corpus luteum)

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

OVULATION

(oocyte and

Corpus luteum)

Progesterone Slows Pulsatile GnRH Secretion

Progesterone

Pituitary

Hypothalamus

Corpus Luteum

Progesterone

As Progesterone Drops, Pulsatile GnRH Increases

And the cycle Starts Again

OocyteCumulus

Granulosa Cells

Theca Cells

Summary of Normal Cycling

1. GnRH is secreted in a pulsatile fashion.

2. FSH stimulates follicle growth and estradiol secretion.

3. High levels of estradiol acutely increase GnRH pulsatility,

resulting in an LH surge and ovulation.

4. Progesterone suppresses GnRH pulsatility to reset the axis.

5. Progesterone withdrawal starts the GnRH pulses again.

Summary of Normal Cycling

1. GnRH is secreted in a pulsatile fashion.

2. FSH stimulates follicle growth and estradiol secretion.

3. High levels of estradiol acutely increase GnRH pulsatility,

resulting in an LH surge and ovulation.

4. Progesterone suppresses GnRH pulsatility to reset the axis.

5. Progesterone withdrawal starts the GnRH pulses again.

6. What does the elevated testosterone in PCOS do to all of this?

Testosterone stimulates GnRH secretion

in the hypothalamus

Testosterone Blocks the Suppressive Effects of

Progesterone on GnRH Pulsatility

Pastor, C. L. et al. J Clin Endocrinol Metab 1998;83:582-590

Pituitary

Hypothalamus

Pulsatile GnRH Secretion is Increased in PCOS

OocyteCumulus

Granulosa Cells

Theca Cells

Pituitary

LH/FSH

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Excess GnRH Stimulates FSH and LH Secretion

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Inhibin Blocks FSH Secretion

Inhibin (-)

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Without Aromatase, LH Stimulates

Ovarian Testosterone Secretion

Testosterone

Inhibin (-)

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Testosterone Further Stimulates GnRH Pulsatility

Testosterone

Inhibin (-)

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

The Vicious Positive Feedback Loop of PCOS

Testosterone

Inhibin (-)

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Without Ovulation, No Progesterone is Made

To Inhibit GnRH Secretion

Testosterone

Inhibin (-)

No Ovulation -

No Progesterone

Excess Androgens from any Source can

Result in PCOS

NORMAL6 YEARS

AFFECTED4 YEARS

AFFECTED2 YEARS

Cholesterol

Pregnenolone

17OH-Pregnenolone 17OH-Progesterone

Androstenedione

Progesterone

CYP11A1 CYP21

Adrenal Source of Androgens:

Congenital Adrenal Hyperplasia

Aldosterone

Cortisol

Cholesterol

Pregnenolone

17OH-Pregnenolone 17OH-Progesterone

Androstenedione

Progesterone

CYP11A1 CYP21

Aldosterone

Cortisol

Increased: Not Increased:

1. Polycystic ovaries 1. Insulin Resistance

2. Ovarian androgen production

3. Infertility

Suggests:

1. Androgens themselves are capable of promoting PCOS.

2. Androgen exposure in-utero may initiate a “program”that results in PCOS.

Exogenous Source of Androgens

1. Anabolic Steroid Abuse

a. More polycystic ovaries and problems with fertility

b. Less insulin resistance

Franke and Berendonk (1997), Hormonal doping and androgenization of athletes:

a secret program of the German Democratic Republic government,

Clinical Chemistry 43, 1262-1279.

2. Female to male transgender patients

a. Increased ovarian size and number of cystic follicles

b. Increased androgen receptor expression in ovary and

uterus

Pache et. al. (1991) Histopathology 19, 445-452

Chadha et. al. (1994) Human Pathology 25, 1198-1204

What about Insulin Resistance?

Relative to mock-treated rats, rats treated with IV insulin for four

weeks had:

1. Abnormal estrus cycles

2. Increased testosterone

3. Decreased progesterone

4. Abnormal Follicular Growth

Chakrabarty et. al (2006) J. Soc. Gynecol. Investig 13, 122-129.

Nestler et. al. (1998) JCEM 83, 2001-2005

The Ovaries in PCOS Patients May be More

Sensitive to Insulin-Stimulated Testosterone

Production

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Insulin and PCOS

Testosterone

Inhibin (-)

Insulin

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Treatment of PCOS

Testosterone

Inhibin (-)

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Testosterone

Inhibin (-)

Treatment of PCOS

Wedge Resection or Ovarian Mining

1. Used since the time of Stein and Leventhal

2. Remove part of ovary to decrease ovarian androgen production

3. Decreased androgen levels will improve symptoms and

hyperandrogenemia and will break the positive feedback to permit

cycling to resume.

Farquhar (2004) Best Practice & Research Clinical Obst. and Gyn. 18, 789-802.

Wedge Resection or Ovarian Mining

4. Can sometimes improve pregnancy rates

5. Many small studies demonstrate success, but never a good,

randomized, controlled study.

6. Long term concerns with surgery include adhesions and an

increased incidence of premature ovarian failure.

Farquhar (2004) Best Practice & Research Clinical Obst. and Gyn. 18, 789-802.

Insulin Sensitizers

1. Metformin and thiazolidinediones

2. Improve insulin sensitivity, which then lowers insulin levels

3. Decreased insulin signaling in the ovary may lower insulin-

mediated steroidogenesis.

4. These drugs may also directly inhibit ovarian steroidogenesis

Insulin Sensitizers

5. Improve cycling and ovulation rates in many patients

6. Improve fertility in some studies.

Insulin Sensitizers Improve Ovulation

Ibanez et. al. (2001) JCEM 86, 3595-3598

Insulin Sensitizers

Ibanez et. al. (2001) JCEM 86, 3595-3598

Insulin: 16.1 to 11.1

BMI=21.4 - no change

Androgen Receptor Blockade

Spironolactone

1. Improves signs of hyperandrogenemia – hirsutism, acne, etc.

2. Cycling can improve over 6-12 months

3. Testosterone and insulin levels can be lower (similar to metformin)

4. Improvements correlate with BMI - better results with lower BMI.

5. Necessary doses range from 50 – 200 mg per day.

6. Not to be used to improve fertility

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

The Ovarian Axis in PCOS

Testosterone

Inhibin (-)

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

The Ovarian Axis in PCOS

Testosterone

Inhibin (-)

Oral Contraceptives

1. High estrogen and progesterone levels suppress GnRH

pulsations, thus lowering LH and testosterone levels.

2. Can use progesterone alone, at it will still suppress GnRH

pulsations.

3. Symptoms of hyperandrogenemia will improve.

4. Will establish regular periods.

5. Not useful if goal is pregnancy.

GnRH Agonists and OCPs Lower Testosterone

Equally Well in Patients with PCOS

Carr et. al. (1995) JCEM 80, 169-1178

Pituitary

Cumulus

Granulosa Cells

Theca Cells

Hypothalamus

Stop the Positive Feedback Loop!

Testosterone

Inhibin (-)

To Best Improve Fertility, Ovulation Induction

is Still the Most Effective

Clomiphene Citrate

1. Estrogen agonist/antagonist (SERM)

2. Start at 50 mg per day for 5 days on 5th day of

3. Increases FSH production and estradiol

production

4. After stopping, surge in estrogen signaling

enhances GnRH pulsatility and LH secretion.

5. Enhanced ovulation

6. Improves fertility better than metformin

Clomiphene Induces Ovulation Better than

Metformin

Legro et. al. (2007) NEJM 356, 551-566

BMI dropped a little in both metformin groups (35 to 34kg/m2)

Insulin levels did not change in any group

Testosterone dropped in both metformin groups (62 to 53 ng/dL)

The higher the BMI, the less effective for all treatments combined

Clomiphene Induces Ovulation Better than

Metformin

To Best Improve Fertility, Ovulation Induction

is Still the Most Effective

Aromatase Inhibitor

1. Take 5 days starting the 3rd day of cycle

(2.5 -5 mg letrozole)

2. Blocks estrogen production

3. Increased FSH production

4. Estrogen surge when drug is stopped

5. Triggers LH release from pituitary

6. Improves fertility

Letrozole Works as Well as Clomiphene in

Inducing Ovulation

Legro et al, N Engl J Med 2014; 371:119-129

If Too Many Androgens Cause Unregulated

Follicle Overgrowth, then What Happens with

Too Little Androgen?

Androgen Receptor Knockout Mice have

Decreased Fertility

Hu et. al. (2004), PNAS 101, 11209-14

Kato (2006), PNAS 103, 224-9

Reduced litter numbers

Reduced Litter sizes

Smaller ovarian follicles

Premature Ovarian Failure

Hypothalamus

Pituitary

Uterus

Theca cells

Granulosa cells

Oocytes

The Follicle

Androgen Receptor is Expressed

Throughout the HPG Axis

Hypothalamus

Pituitary

Uterus

Theca cells

Oocytes

The Follicle

Granulosa cells

Androgen Receptor is Expressed

Throughout the HPG Axis

Loss of AR in Granulosa Cells Results in:

Reduced litter numbers

Reduced Litter sizes

Smaller ovarian follicles

Premature Ovarian Failure

Sen and Hammes (2010) Molecular Endocrinology 24, 1393-403

Androgens Promote Follicle Growth

and Prevent Follicle Atresia

Primary Pre-Antral Antral Ovulation

Corpus Luteum

Primordial

Atresia

Sen and Hammes (2010) Molecular Endocrinology 24, 1393-403

Sen and Hammes (2014) PNAS 111, 3008-13

Ma, Hammes, and Sen (2017) Endocrinology 158, 2944-2954

Sunkara and Coomarasamy (2011), Fertility and Sterility 95, 73-74

DHEA Treatment in Patient with

Diminished Ovarian Reserve Might

Improve Pregnancy Rate

“Balance is Key”Mr. Miyagi

Too many androgens: PCOS

Too few androgens: Diminished Ovarian Reserve

Summary

1. Androgens are important for normal ovarian function.

2. Too many androgens leads to PCOS, a common disease that is

becoming even more prevalent.

3. Too few androgens may lead to diminished ovarian reserve.

4. PCOS is accompanied by significant co-morbidities, including the

metabolic syndrome and insulin resistance.

5. Etiologies of PCOS are diverse; however, the result is a powerful

positive feedback loop involving neuronal and ovarian signaling.

6. Treatment strategies for PCOS should focus on goals and

expectations of the patient.

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