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  • Nathan Riley, MD

Obgyno Wino Podcast Episode 2 - Polycystic Ovarian Syndrome

Updated: Jul 20, 2019

“Medicine is not only a science; it is also an art. It does not consist of compounding pills and plasters; it deals with the very processes of life, which must be understood before they may be guided.” ― Paracelsus

2016 Wintner’s Collection Merlot from Sterling Vineyards

PB#194 - Published June 2018

Diagnosis

- there is no universally accepted definition or set of diagnostic criteria

- in the past, there was Rotterdam criteria, NIH criteria, and Androgen Excess Society all differ slightly

- NIH requires hyperandrogenism and oligomenorrhea

- Rotterdam requires 2 of 3: hyperandrogenism, oligo, and polycystic ovaries on sono

- AES requires hyperandrogenism and 1 of 2: oligo and polycystic ovaries on sono

- all require that secondary causes be ruled out (e.g. adult-onset congenital adrenal hyperplasia, androgen-secreting tumor, or hyperprolactinemia)

- insulin resistance and obesity are often seen in PCOS, but note that they are not included in any of these criteria


Etiology remains unknown

- might be insulin resistance: as tissues become resistant to insulin, insulin levels are ramped up by the pancreas, which acts at the liver to decrease circulating levels of SHBG resulting in higher levels of circulating androgens

- insulin may also directly act upon the hypothalamus to influence gonadotropin secretion

- obesity has been hypothesized as a driving force, but up to 20% of patients w/ PCOS are not obese


Clinical manifestations

- menstrual irregularity, infertility, hirsutism, acne

- higher risks of ovarian hyperstimulation syndrome and multi-gestation pregnancy if they undergo ovulation induction

- when pregnant, they also have higher risk of GDM and hypertensive disorder in pregnancy

- great risk for metabolic syndrome, fatty liver, sleep apnea, obesity, type 2 diabetes, CVD, ?mood disturbances (due to all of these associations, comprehensives lab workup recommended, see Box 1) - total testo, free testo, SHBG, TSH, prolactin, 17hydroxyprogesterone, screen for diabetes, etc.


Before we move on...

- Review of metabolic syndrome (need 3 of 5):

> BP ≥130/85 mmHg

> Waist circumference ≥35 in

> Fasting glucose ≥100 mg/dL

> HDL ≤50 mg/dL

> Triglycerides ≥150 mg/dL

Sonographic appearance of polycystic ovaries

DDx

- history: menstrual history, medications, exogenous androgen use, fhx of diabetes and CVD

- balding, acne, hirsutism (upper lip, chest), clitoromegaly, enlarged ovaries, obesity, htn, acanthosis nigricans

Cushing’s

- not necessary to test for Cushing’s in every patient with evidence of hyperandrogenism

- indicated if other signs of Cushing’s (moon facies, buffalo hump, abdominal striae, central adiposity, or HTN)

- test: 24 hr urinary free-cortisol or low dose dex stimulation test


Androgen-secreting tumors

- diagnosis can be challenging

- in the past, elevated testo or DHEAS levels were used to evaluate for these tumors, but the previous cutoff serum levels had low specificity and sensitivity

- the present recommendation by the AES is to measure SHBG and free testo

- apparently, the analytical performance of the assays used by laboratories across the US differ widely, so testing for these tumors can be highly unreliable

- evidence of high DHEAS can be helpful in evaluating rapid virilization (as it originates in the adrenals) but it’s not that useful in evaluating common hirsutism

**RECALL: adrenals and ovaries produce androgens

- from adrenals: DHEA (Dehydroepiandrosterone) or DHEAS - weak, but can be converted to more potent hormones testosterone or dihydrotestosterone (DHT, most potent, but of negligible quantities in women)

- primary production is in the ovaries: testosterone, androstenedione (fun fact: androstenedione is the only androgen present in higher quantities in premenopausal women than in men)


Nonclassical congenital adrenal hyperplasia (aka “late onset”)

- classic duo: anovulation and hirsutism

- secondary to defect in 21 hydroxylase (CYP21)

- common in Ashkenazi Jews, should also consider screening Hispanics, Yugoslavs, Native American Inuits in Alaska, and Italians

- screen by checking morning 17-hydroxyprogesterone (<2 ng/mL is normal, <4 in the follicular phase), specificity decreases in luteal phase

- if high, perform an ACTH stimulation test

**Remember that? Cortisol levels are checked before and 1-hour after injecting ACTH; if pituitary-adrenal axis is functioning properly, you’ll see an increase in cortisol)

Remember me?

What effect does weight loss have on fertility in PCOS?

- in obese patients w/ PCOS, weight loss --> decreased serum androgens through decreased peripheral conversion and, as a result, improvement of the endocrine and menstrual abnormalities

RECALL: androstenedione is aromatized to E1, which is then converted to E2 by 17β-hydroxysteroid dehydrogenase

- aromatase found in placenta, skin, breast, fat, brain, and granulosa cells (ovary)

- 17β-hydroxysteroid dehydrogenase found in fat, liver, theca cells (ovary)

- recall: estrogen review

- E1: highest conc in menopause

- E2: most biologically active

- E3: predominates in pregnancy, least potent, created from E1 or E2 by 16α-hydroxylase in liver


PCOS and CVD

- dyslipidemia is common, particularly elevated LDL

- diet and exercise are king

- no prospective studies have found an increased risk of cardiovascular events in PCOS, though cohort studies have found an increased risk of CVD or cardiac events in the presence of oligo or other PCOS-associated symptoms in menopausal women


PCOS and diabetes

- 2-5x higher risk of DM in PCOS pts

- screen for diabetes

RECALL: fasting + 2-hr post 75-gm load

- fasting >126 diagnostic

- ≤140 after 2 hr is normal, 141-199 impaired, ≥200 diagnostic

Two big issues with PCOS: menstrual disorders, metabolic derangements, and infertility:

Menstrual disorders and metabolic derangements (including CV risk reduction)


Lifestyle modification

- best approach

- per ACOG, caloric restriction rather than the composition of the diet is the key factor

- (based on studies which have shown no preference for a particular hypocaloric diet)

- anecdotally, Ill throw my two cents in: sugar is generally going to be the problem. If you can go into a caloric deficit by eating less and exercising despite eating a mostly low nutritient, sugar-laden diet, you’re going to find yourself very hungry and dieting will be a nightmare

- more veggies, more avocado, more olive oil, less cake, cookies, and soda


COCs in treating menstrual disorders

- combined pills suppress pituitary LH secretion, ovary androgen secretion, and increase circulating SHBG

- as various COC have varying combinations of estrogen doses and progestin preparations, risk-benefit ratios vary

- no evidence to guide selection of COC to treat menstrual disorders in women w/ PCOS


COCs in treating metabolic derangements

- no convincing evidence to suggest an increased risk of adverse effects from these meds on diabetes and CV risk in women, so safe for consideration

- they haven’t been found to increase risk of diabetes in PCOS, though there have been some observed effects on insulin sensitivity at higher doses, therefore low dose pill is recommended

- transient increase in triglycerides and HDL

- bottom line: not useful in modifying metabolic risk factors


Progestins stink at treating menstrual disorders or metabolic derangements

- Progestin-containing IUDs or progestin-only contraceptives can be considered for endometrial protection in PCOS patients, but they are associated with abnormal bleeding patterns in 50-90% of users

- Statins have no benefit in young women, especially adolescent girls


Ovulation induction!!

ASRM and ESHRE position

- before turning to medication, ASRM (American Society for Reproductive Medicine) and ESHRE (the European Society of Human Reproduction and Embryology) recommend emphasis on weight reduction, smoking cessation, and reduction of alcohol consumption.


Clomiphene citrate

- long-held first-line treatment as it has been shown through multiple studies to perform better than placebo or metformin alone

- Start at 50 mg, as 50% of women who will find success with this dose; 70% will find success with 100 mg dose

- how: 50mg /day for 5 day started starting day 3,4,or 5 after menses or a progestin-induced bleed, 5-7 days later, an ultrasound will be performed to evaluate the follicles and anticipate ovulation and thus timing for intercourse.

- if it’s going to work, it will likely work within 6 ovulatory cycles, but it’s reasonable to continue trying beyond the 6 months

- if patients still don’t get pregnant, you can consider adding Dexamethasone during the clomiphene citrate induction


Recall

-- Progestins like Medroxyprogesterone (Provera) can mimic the activities of the corpus luteum in a normal menstrual cycle. Remember that the menstrual cycle is split into two parts: follicular phase and luteal phase. During the follicular phase, gonadotropins secreted from the pituitary gland stimulate the development of follicles within the ovary. Eventually, one of the follicles predominates. Ovulation occurs as response to an LH surge, and the remaining corpus luteum produces high quantities of progesterone, which helps to prepare the endometrium for blastocyst implantation. If conception doesn’t occur, the corpus luteum degenerates, and the cessation of progesterone causes a “withdrawal” bleed due to sloughing of the endometrium. Provera-induced bleeds work like this. A patient takes 5-10 mg of Provera for 5-10 days. After completing the course, the endometrium sheds as it would if the corpus luteum had degenerated. This starts the cycle anew. In infertility patients, a provera-induced bleed can be used as a jump-off point to time ovulation induction through clomiphene citrate or aromatase inhibitors like Letrozole. --


Aromatase inhibitors (Letrozole)

- traditionally Clomiphene citrate was preferred, but Cochrane review has found that Letrozole (aromatase inhibitor) resulted in better ovulation rates, pregnancy rates, and live-birth rates than Clomid

- Letrozole should be considered first-line for ovulation induction in pts w/ PCOS

- it’s not FDA-approved for ovulation induction, though

- contraindicated in pregnancy

- same procedure as with clomiphene citrate, only it’s 2.5 mg daily for 5 days

- if no ovulation thereafter, increase to 5 mg/day (max 7.5 mg/day - higher doses can lead to thinning of the endometrium)

- both meds are associated with increase risk of multi-gestation pregnancy (comparable to one another)


Gonadotropins

- REMINDER: This isn’t meant to be a whole course on infertility, so keep in mind that these recommendations are meant by ACOG to be applied to patients with PCOS

- if a patient fails clomiphene citrate, low dose gonadotropin therapy is an option

- low-dose regimens are better in PCOS as they carry a lower risk for ovarian hyperstimulation syndrome (due to the higher number of follicles in the ovaries of PCOS, these pts are at higher risk for OHSS)


Ovarian drilling

- should be considered 2nd line therapy

- interestingly, the benefits on fertility are short-lived, and adjuvant therapy with clomiphene citrate or gonadotropins is often required

- not surprising: no benefits to metabolic abnormalities


Insulin-sensitizing agents (special section here at the end because they actually have a role in correcting metabolic derangements AND fertility issues)

- two types: biguanides and thiazolidinediones

- biguanides (metformin): decrease weight, risk of lactic acidosis particularly in poorly controlled diabetes with impaired renal function; can also cause GI distress (ameliorated by gradual uptitration)

- thiazolidinediones (pioglitazone and rosiglitazone): increase weight

- improvement in insulin sensitivity is associated w/ a decrease in circulating androgen levels, improved ovulation rate, and improve glucose tolerance

- due to improvement in ovulation rate, be sure to discuss contraception


Insulin-sensitizing medications in treating metabolic derangements

- metformin has been looked at but not the thiazolidinediones

- metformin is associated with improved, sustained glucose tolerance

- results are inconsistent as to whether or not it contributes to sustained weight loss

- all in all, little additional benefit when added to lifestyle modifications

- none of these agents will prevent diabetes


Insulin-sensitizing medications in treating infertility

- RCTs haven’t panned out to support metformin as first-line infertility therapy

- clomiphene citrate works 3x as well

- having said that, a meta-analysis done in 2008 suggests that clomid + metformin might be a more effective combo than either alone in obese PCOS patients

- metformin is safe in pregnancy but won’t prevent pregnancy loss


What about hirsutism doc?

- Depo-Provera or intermittent oral Provera: nope

- anti-androgens: maybe mildly effective, though not FDA approved for this use

- Spironolactone: COC w/ anti-androgenic properties: best bet (give 25-100 mg BID, increase PRN but look out for orthostatic hypotension)

- Flutamide (androgen-receptor agonist - competes with androgens at androgen receptors): works 125-250 mg/day

- Finasteride (inhibits 5-a-reductase: converts testo to dihydrotestosterone): works well and with less renal and hepatic toxicity

- Metformin or thiazolidinedione: nopers

- Lastly, Eflornithine (inhibits ornithine decarboxylase); topical cream applied twice daily to affected areas, works well but not in women of African descent

- PB notes that Antiandrogens, spironolactone, flutamide, finasteride can be feminizing in male fetuses if inadvertently used in pregnancy

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