PCOS Management and Updates

Rotterdam Criteria Revisions

  • The original Rotterdam criteria for Polycystic Ovarian Morphology (PCOM) on ultrasound involved the presence of 12 or more follicles, sized between 2-9mm (less than 1cm), or an ovarian volume exceeding 10ml in at least one ovary. These criteria, established for diagnosing PCOS, have been widely used but also subject to revisions to improve diagnostic accuracy.

  • Due to the common observation of \geq 12 follicles, revisions have been recommended to prevent overdiagnosis of PCOS. The original threshold was found to be too sensitive, leading to many women being misdiagnosed with PCOS. This overdiagnosis can result in unnecessary anxiety and medical interventions.

  • Williams Gynecology, 4th edition, mentions revisions by the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM). These revisions aim to refine the diagnostic criteria to better reflect the underlying pathophysiology of PCOS and improve the specificity of the diagnosis.

Revised Diagnostic Criteria for PCOM

  • ESHRE/ASRM criteria: Defines PCOM as \geq 20 follicles of 2-9mm size or an ovarian volume > 10 ml. This revision raises the threshold for the number of follicles, aiming to reduce the rate of false-positive diagnoses. The increased number helps in differentiating between normal ovarian findings and true PCOM.

  • Androgen Excess & PCOS Society (AEPCOS) criteria: Defines PCOM as \geq 25 follicles. AEPCOS provides an even stricter criterion, further minimizing the chances of misdiagnosis and focusing on women with a more pronounced polycystic ovarian morphology.

  • It's important to note which criteria are referenced in questions about PCOS.

    • Rotterdam criteria: \geq 12 follicles.

    • ESHRE/ASRM criteria: \geq 20 follicles.

    • AEPCOS criteria: \geq 25 follicles. When evaluating a patient or interpreting research, knowing which criteria were used is essential for accurate assessment and comparison.

Management of PCOS: Lifestyle Modification

  • First-line management: Lifestyle modification, including weight loss, is the primary approach. This is universally recommended for overweight or obese women with PCOS because it addresses the underlying metabolic and hormonal imbalances associated with the condition.

  • Even a modest weight loss of 5-10% can restore ovulatory cycles in 5-10% of women with PCOS. This seemingly small amount of weight loss can have significant impacts on reproductive and metabolic functions, highlighting the importance of lifestyle interventions.

  • Benefits of weight loss:

    • Decreases central fat. Central obesity is strongly linked to insulin resistance and hormonal imbalances in PCOS. Reducing central fat can improve these metabolic disturbances.

    • Improves insulin sensitivity. Enhanced insulin sensitivity helps regulate blood sugar levels and reduces the compensatory hyperinsulinemia that drives androgen production.

    • Increases sex hormone-binding globulin (SHBG), which reduces free androgen levels. Higher SHBG levels bind more free testosterone, lowering the circulating levels of androgens and alleviating symptoms like hirsutism and acne.

  • Mechanism: Insulin resistance causes high insulin levels, which in turn decrease SHBG. Weight loss improves insulin sensitivity, lowering insulin levels and increasing SHBG, thus reducing free testosterone. This mechanism is central to understanding how lifestyle changes impact PCOS symptoms.

  • Weight loss is primarily recommended for overweight or obese PCOS patients through a hypocaloric diet, exercise, and brisk walking. Combining these approaches maximizes the benefits for weight management and metabolic improvement.

  • Metformin: Although metformin can assist with weight loss by improving insulin resistance, it's not prescribed solely for weight loss. Metformin's primary role is to improve insulin sensitivity, which can indirectly support weight loss efforts.

Bariatric Surgery Considerations

  • Following bariatric surgery, rapid weight loss occurs within 1-2 years. This rapid change can have profound effects on metabolic and reproductive health.

  • Conception during this period can lead to Intrauterine Growth Restriction (IUGR) and nutritional deficiencies for both the mother and the fetus. Rapid weight loss can mobilize toxins and nutrients, potentially harming fetal development.

  • Females are advised to conceive after 1-2 years post-bariatric surgery. Waiting allows the body to stabilize, reducing the risks associated with rapid weight loss and nutritional deficiencies.

Drug of Choice in General: Oral Contraceptive Pills (OCPs)

  • While management depends on the specific problem a patient presents with, combined oral contraceptive pills (OCPs) are generally the drug of choice for PCOS. OCPs are versatile and can address multiple symptoms of PCOS, including menstrual irregularities and hyperandrogenism.

  • The progesterone component in OCPs should be from the third or fourth generation due to their lower androgenic side effects. Newer generation progestins are less likely to exacerbate androgenic symptoms like acne and hirsutism.

  • Rationale: OCPs address menstrual irregularities (oligo-ovulation) common in PCOS. By providing exogenous hormones, OCPs regulate the menstrual cycle and reduce the risk of endometrial hyperplasia.

  • Mechanism: OCPs containing exogenous estrogen and progesterone exert negative feedback on natural FSH and LH, suppressing ovulation. This suppression helps to regulate hormone levels and reduce androgen production by the ovaries.

  • The pills are typically administered for three weeks followed by a one-week break to induce menstruation. This regimen mimics a normal menstrual cycle, providing hormonal stability and regular bleeding.

Benefits of OCPs in PCOS

  • Cycle Regularization: OCPs, given in a 3-week on, 1-week off cycle, regularize menstrual cycles. This is particularly beneficial for women with infrequent or absent periods.

  • Hirsutism Treatment: Progesterone in OCPs reduces endogenous LH levels, decreasing androgen production by theca cells. Lower androgen levels can help alleviate hirsutism and acne.

  • Endometrial Protection: OCPs decrease endogenous estrogen levels, thinning the endometrium and reducing the risk of endometrial hyperplasia. By controlling endometrial growth, OCPs help prevent precancerous changes.

Management of Menstrual Irregularity

  • Definition of Oligo-ovulation/Oligomenorrhea: Less than nine cycles per year. This definition helps in identifying women who may benefit from interventions to regulate their menstrual cycles.

  • Drug of choice: Oral contraceptive pills (OCPs). OCPs are effective in regulating cycles and protecting the endometrium.

  • Alternatives: Estrogen and progesterone patches or rings, applied for three weeks and removed for one week. These alternatives provide a convenient and non-oral route of hormone administration.

Progesterone Withdrawal

  • If OCPs are contraindicated or unwanted, progesterone withdrawal can be used every 1-3 months. This approach can induce regular bleeding without the need for continuous OCP use.

  • Method: Medroxyprogesterone acetate (5-10mg daily orally for 12 days) or micronized progesterone (200mg orally for 12 days). These regimens provide sufficient progesterone to induce withdrawal bleeding.

  • Important Note: Progesterone withdrawal does not act as a contraceptive and does not alleviate acne or hirsutism; it only induces menstruation. Women need to be informed that additional treatments may be necessary for other PCOS symptoms.

Management of Insulin Resistance

  • Drug of choice: Metformin, a category B drug during pregnancy. Metformin improves insulin sensitivity and can help regulate menstrual cycles and reduce androgen levels.

  • Indications: Impaired glucose tolerance, elevated fasting insulin levels, acanthosis nigricans, or a family history of diabetes mellitus. These factors indicate the presence of insulin resistance and support the use of metformin.

  • Dosage: 850mg BD or 500mg TDS, administered with meals to reduce gastrointestinal side effects. Taking metformin with food can minimize common side effects like nausea and diarrhea.

  • Important Notes: Metformin is not teratogenic. This is reassuring for women who are considering pregnancy.

Metformin During Pregnancy

  • Studies suggest that metformin during pregnancy in PCOS patients with insulin resistance may reduce the risk of abortion and gestational diabetes. These potential benefits are being actively researched.

  • However, it is not yet a recommended indication; metformin use is currently only recommended for insulin resistance. More evidence is needed before metformin is routinely prescribed during pregnancy for PCOS.

Glucose Tolerance Testing in PCOS

  • It's recommended that all PCOS patients undergo a 75-gram oral glucose tolerance test (OGTT) every two years to screen for insulin resistance or type 2 diabetes mellitus. Regular screening is essential due to the increased risk of these conditions in women with PCOS.

  • If fasting insulin levels are \geq 20 milli international units or 2-hour postprandial (2hrPP) insulin levels are \geq 55 milli international units, insulin resistance is indicated. These values help in identifying women with significant insulin resistance.

  • In patients with insulin resistance, 75-gram OGTT should be repeated yearly rather than bi-yearly. More frequent monitoring is necessary to manage and prevent the progression of insulin resistance.

  • OGTT values in non-pregnant females: Fasting should be <100, 1hrPP should be <200, and 2hrPP should be <140. These values provide a benchmark for assessing glucose metabolism.

Alternative Drugs for Insulin Resistance

  • Other insulin sensitizers like GLP-1 receptor agonists (glucagon-like peptide 1 receptor agonist) and empagliflozin (sodium-glucose cotransporter-2 inhibitor) can be used. These drugs offer alternative mechanisms for improving insulin sensitivity.

  • However, these are category C pregnancy drugs and are not preferred if the patient desires to conceive. Metformin remains the drug of choice due to safety. These drugs are generally avoided in women planning pregnancy due to potential risks.

Management of Hirsutism

  • Mild Hirsutism: Advise mechanical hair removal methods such as shaving, plucking, waxing, or laser. These methods are effective for managing mild cases of excess hair growth.

  • Moderate to Severe Hirsutism:

    • Moderate: Ferriman-Gallwey score \geq 10

    • Severe: Ferriman-Gallwey score \geq 15

    • Drug of Choice: Oral combined pills (OCPs) with a fourth-generation progesterone (drospirenone or cyproterone acetate). These OCPs are preferred due to their anti-androgenic effects.

Oral Contraceptive Pills (OCPs) for Hirsutism: Mechanism

  • Estrogen in OCPs increases sex hormone-binding globulin (SHBG), reducing free testosterone levels. This helps to decrease the amount of testosterone available to bind to androgen receptors.

  • Exogenous progesterone has a negative feedback on LH, reducing androgen production. This further lowers androgen levels, reducing hirsutism.

  • Examples available in India: Diene 35 and Dianet. These are specific brands of OCPs commonly used in India for managing hirsutism.

  • For patients with contraindications to estrogen (e.g., a history of venous thromboembolism), norethindrone can be used. Norethindrone is a progestin-only option that avoids the risks associated with estrogen.

Duration of Treatment and Second-Line Management

  • The total duration of action with OCPs for hirsutism should be six months due to the half-life of hair follicles. This allows sufficient time to see a noticeable reduction in hair growth.

  • If no desired effect is achieved after six months, second-line management with antiandrogens (e.g., spironolactone) is considered. This step-wise approach ensures that more potent medications are used only when necessary.

Second-Line Management for Hirsutism

  • Antiandrogens: Spironolactone (50-100mg BD).

  • May be used separately or in combination with OCPs. Combining treatments can be more effective in reducing androgen levels.

  • Adverse effects of spironolactone: orthostatic hypotension and hyperkalemia, and caution is needed in females with decreased renal function. Monitoring is important to manage these potential side effects.

  • Alternatives: flutamide, finasteride, ketoconazole. These drugs offer alternative mechanisms for reducing androgen effects.

  • Last resort: continuous GnRH. This is reserved for severe cases unresponsive to other treatments.

Topical Treatment Option

  • Topical eflornithine (a reversible inhibitor of ornithine decarboxylase) slows facial hair growth with long-term use. This topical cream can be applied directly to areas of excess hair growth.

  • Danazol should never be used for treating hirsutism as it can cause hirsutism as a side effect. This paradoxical effect makes danazol unsuitable for hirsutism treatment.

  • Treatment for hirsutism is generally indefinite or until the female desires to conceive due to the recurring nature of excess hair. Ongoing management is often necessary to maintain results.

  • Avoid pregnancy while on antiandrogens due to the risk of ambiguous genitalia in a male fetus. Effective contraception is essential when using these medications.

Alopecia (Hair Loss)

  • Check testosterone levels first. Elevated testosterone can be a cause of hair loss in women with PCOS.

  • If alopecia is due to hyperandrogenism: OCPs + antiandrogens. This combination can help reduce androgen levels and promote hair regrowth.

  • If androgen levels are normal: finasteride (decreases dihydrotestosterone levels) or minoxidil (side effect is headache). These medications can address hair loss through different mechanisms.

Management of Infertility

  • Infertility in PCOS is primarily due to anovulation, but egg quality and endometrial receptivity may also be reduced. Addressing these factors is crucial for improving fertility outcomes.

  • Drug of choice for treating infertility in PCOS: Ovulation inducing drugs, first line is letrozole. The second choice is Clomiphene citrate.

  • Second-line drugs: HMG (75 international units of LH and FSH), laparoscopic ovarian drilling, pulsatile GnRH, and IVF.

Key Points on Ovulation Induction

  • Drug of choice for anovulation in PCOS: Letrozole.

  • Drug of choice for anovulation (general): Clomiphene citrate.

  • Drug of choice for unexplained infertility: Clomiphene citrate + IUI (Intrauterine Insemination).

  • Drug used for ovulation stimulation during IVF: HMG.

Letrozole and Clomiphene Citrate: Mechanisms

  • Clomiphene Citrate:

    • Selective estrogen receptor modulator (SERM) acting as an estrogen antagonist.

    • Decreases estrogen levels, disrupting negative feedback on GnRH, leading to increased LH and FSH.

  • Letrozole:

    • Aromatase inhibitor, preventing the conversion of androgens to estrogens.

    • Also decreases estrogen levels, increasing GnRH and FSH.

    • However, the increase of FSH with letrozole is lower than with clomiphene.

Letrozole vs. Clomiphene Citrate

  • T half of letrozole: 48 hours.

  • T half of clomiphene: much longer, in weeks.

  • Starting dose for letrozole 2.5mg, up to 7.5mg max.

  • Starting dose for clomiphene is 50mg, up to 150mg max.

  • Both given from day 2 to day 5 of cycle for four days.

Monitoring and Ovulation Trigger

  • Before starting treatment: Ultrasound to check for follicular cysts and endometrial thickness (should be < 5mm).

  • Follicular monitoring from day 10: Check the growth of follicles (1-3mm per day).

  • Ovulation trigger: Injection hCG (5,000 international units) when the follicle reaches 18-20mm.

  • Ovulation occurs about 36 hours after hCG injection.

Outcomes with Letrozole and Clomiphene

  • Letrozole leads to more ovulation, higher chances of singleton pregnancy, and a higher live birth rate compared to clomiphene citrate.

    As far as twin pregnancy rates are concerned, I told you they are roughly the same with letrozole and clomiphene citrate. With letrozole the twin pregnancy chances are three to seven percent and with clomiphene citrate they are five to eight percent. This is given on page number ten seventy nine in the latest edition of Leon Spiroff.

  • Pregnancy loss rates are similar with both drugs.

Side Effects and Considerations

  • Most common side effect of clomiphene: Hot flushes.

  • Other side effects of clomiphene include ovarian cysts and visual disturbances (discontinue if visual disturbances occur).

  • Side effects of letrozole: headache, cramps, dizziness, and fatigue.

  • Letrozole: does not lead to any teratogenic effects in the fetus and that is why the ban has been uplifted and that is why now it is not banned.

  • Use letrozole/clomiphene for 3-6 cycles.

Adjuvant Therapies

  • Prednisolone (5mg) can be added if DHEA levels are high.

  • Metformin can be added if insulin resistance is present.

  • Clomiphene is a category X drug during pregnancy, so its use is not recommended.

HMG (Human Menopausal Gonadotropin)

  • Second-line drug: 75 international units of LH and FSH

  • Most common ovulation inducing drug for IVF cycle

  • Indications:

    • Clomiphene or letrozole failure.

    • Ovulation induction in IVF cycles.

    • Hypogonadotropic hypogonadism (e.g., Kallmann syndrome).

  • Letrozole/clomiphene can only be used if the hypothalamic-pituitary-ovarian axis that needs for Clomiphene to work. In hypogonadotropic hypogonadism, the drug of choice becomes injection, HMG. Also in unexplained infertility, I may use HMG.

Risks of HMG

  • Associated with the highest incidence of multi-fetal pregnancy (triplets or quadruplets), as high as 15%.

  • Increased risk of ovarian hyperstimulation syndrome (OHSS).

  • Maximum chances of pregnancy loss.

  • No risk of congenital anomalies; HMG not teratogenic.

HMG Protocol

  • In IVF: Controlled ovarian stimulation using injection HMG (starting dose is 75 international units per day).

  • Monitor estradiol levels and adjust HMG dosage to lead to development of multiple follicles using a step-up protocol.

  • Each follicle releases 200 picograms of estrogen.

  • Estradiol levels and TVS for monitoring of HMG given high likelihood for OHSS with that medication

  • When more than \geq 3 follicles reach \geq 17 mm in diameter, administer injection hCG for ovulation trigger.

    *Given for an average of 7 to 12 days

  • Ideal estradiol levels are 500 to 1,500 picogram per ml.

Factors Influencing Multi-Fetal Pregnancy with HMG

  • Increased estradiol levels.

  • Increased number of developing follicles.

  • Decreased maternal age.

  • Multi-fetal pregnancies with HMG correlate with the total number of follicles, not the size.

  • The number of follicles which is directly related to OHSS.

Laparoscopic Ovarian Drilling

  • Involve burning the ovarian stroma using cautery or laser.

  • Used to decrease the number of theca cells in the ovarian stroma, consequently decreasing the level of hormones/androgens being produced.

  • It is just for theoretical importance. It doesn't have any clinical importance. You will not see anyone doing laparoscopic ovarian drilling these days

  • Can lead to ovarian failure or adhesion formation if overdone.

  • Theoretical Rule of Four: Four punctures and Four seconds at forty watt

IVF in PCOS

  • Mostly in cases in which the patient's age is more than 35 and if she has PCOS and along with PCOS, she has other factors responsible for infertility, then yes, the best answer would be IVF.

Ovarian Hyperstimulation Syndrome (OHSS)

  • Iatrogenic complication most commonly seen with injection HMG or with Clomiphene and not related to Letrozole, the triggering agent is injection HCG

  • Pathophysiology:

    • Large number of follicles are formed, increasing FSH.

    • Following rupturing and using an ovulation trigger drug (HCG), they release vascular endothelial growth factor (VEGF).

    • Increases capillary permeability, leading to extracellular fluid collection (ascites and hydrothorax).

    Decreases vascularity, increasing serum congestion of blood

    • Increased estrogen levels by the use of HCG levels

    *Patient will commonly complain of Abdominal pain

    *OHSS is generally a clinical diagnoses

  • The 5 classes are 1. Abd distention, grade 2. nausea/vomiting and ovary enlargement 5-12cm which on ultrasound, grade 3. Ultrasound has ovary enlargement plus ascites, grade 4. have clinical evidence of ascites and hydrothorax and grade 5 there is decreased renal flow

  • If it is simply grade 1 or grade 2 then conservative treatment and tell them to avoid Inter course

Management of OSSS patient that has been detected

  • Mild disease just needs supportive treatment with analgesics for pain, avoid Inter course and strenuous activity

    *Maintain electrolyte and keep fluid balance for high level cases

  • Use Isotonic fluids like normal saline. can get prophylaxis for embolisms and paracentesis for ascites cases

  • The patient will likely get worse if they Conceive, which will lead to continuous production of HCG which they already have in excess

  • Trigger point: early means less than 9 days of injection triggering agent. late means pregnancy triggered it with the egg attaching to walls (called ENDOGENOUS HCG PRODUCTION)

Risk Factors for OSSS

Patient: be aware of age being generally less than 10 and thinner and will have a prior history of OSSS

Ovary: Look for cases, where if small/intermediate, then large numbers of follicles are present. Increase Antimullarian and level of growing hormones

HCG