01-13 The polycystic ovary

Lesson 13 of 15

The polycystic ovary

Pilar Alamá, MD, PhD Gynecologist Director of Oocyte Donation Program IVI Valencia

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IntroductionPathology Clinical implicationsSterility Conclusions

Introduction

• The polycystic ovary syndrome affects 8-13% women in fertile age

• Ovaries with a polycystic appearance are present in 15-20% of healthy women.
• It is a metabolic and reproductive alteration.

• Associated with hyperandrogenism, insulin resistance and obesity.
• Entity with a frequent family association. Several hypotheses are considered:

• Dominant autosomal inheritance.
• Transmission linked to the X-chromosome.
• Polygenic inheritance.

Introduction

Clinical manifestations

• Ovulation disorders in 70% of cases:
• Delayed menarche
• Oligomenorrhea (6–8 menstrual cycles per year)
• Amenorrheic intervals (19.2%)
• Dysfunctional uterine bleeding

• Hyperandrogenism (70%): hirsutism, acne, seborrhea, alopecia
• Infertility (anovulation): 60–70%
• Insulin resistance: 50–70%
• Overweight/obesity: 50–60%
• Poor prognosis factor

• In women with BMI < 25 kg/m2, prevalence 4.3%
• If BMI > 30 kg/m2, prevalence 14%

Introduction

Clinical manifestations - PCOS: changing women´s health paradigm

Introduction

Diagnostic criteria

Rotterdam 2003 2 out of 3 are required

NIH 1990 All are required

AES 2006 All are required

• Menstrual irregularity due to an oligo or anovulation.
• Clinical and/or biochemical hyperandrogenism.

• Oligo or anovulation.
• Clinical and/or biochemical hyperandrogenism.
• Polycystic ovary on the ultrasound.

• Ovarian dysfunction - oligo/anovulation and/or polycystic ovaries on the ultrasound.
• Clinical and/or biochemical hyperandrogenism.

Exclusion of other entities

Introduction - no audio

Diagnostic criteria

The role of each phenotype remains unclear; however, studies that associate hyperandrogenism with metabolic dysfunction might actually be reflecting the effect of adiposity in these patients.

Introduction - no audio

Diagnostic criteria

Introduction - no audio

Diagnostic criteria - Irregular cycles

Clinical hyperandrogenism

Biochemical hyperandrogenism

Irregular cycles

Ultrasound

• They are normal during the first year after menarche.
• Between 1 and 3 years post-menarche: cycles shorter than 21 days or longer than 45 days.
• From 3 years post-menarche until perimenopause: cycles shorter than 21 days or longer than 35 days, or fewer than 8 cycles per year.
• More than 1 year after menarche: any cycle lasting more than 90 days.
• Primary amenorrhea: absence of menstruation by age 15 or more than 3 years after thelarche (onset of breast development).
• In the presence of irregular cycles, the possibility of polycystic ovary syndrome (PCOS) should be considered, and evaluation should follow current clinical guidelines.
• Ovulatory dysfunction may occur even in women with regular cycles. If anovulation is suspected, serum progesterone levels should be assessed.

Introduction - no audio

Diagnostic criteria - Biochemical hyperandrogenism

Clinical hyperandrogenism

Biochemical hyperandrogenism

Irregular cycles

Ultrasound

• The role of biochemical hyperandrogenism becomes relevant when clinical hyperandrogenism is unclear.
• For the diagnosis of biochemical hyperandrogenism, the following assessments should be performed:
• Measurement of total and free testosterone in blood for diagnostic purposes.
• If these are not elevated, androstenedione and dehydroepiandrosterone sulfate (DHEAS) can be measured, although they are less specific and play a limited role in the diagnosis of PCOS.
• A reliable assessment of biochemical hyperandrogenism is not possible while on hormonal contraceptives. Discontinuation for ≥ 3 months with alternative contraception should be considered.
• When androgen levels are well above laboratory reference ranges, other causes should be investigated.

Introduction

Diagnostic criteria - Clinical hyperandrogenism

Clinical hyperandrogenism

Biochemical hyperandrogenism

Ferriman-Gallway score

Irregular cycles

Ultrasound

• A thorough medical history and physical examination are essential.

• In adults: acne, female-pattern hair loss, and hirsutism.
• In adolescents: severe acne and hirsutism.

• Standardized visual scales are preferred, including the modified Ferriman–Gallwey (mFG) score; a score of ≥ 4–6 indicates hirsutism.

• Mild hirsutism: 0–15.
• Moderate: 16–25.
• Severe: above 25 (maximum score: 36).

The modified Ferriman-Gallwey classification is used to assess the degree of hirsutism. A thorough medical history and physical examination are essential. In adult women, acne, female-pattern hair loss, and hirsutism are evaluated, while in adolescents, severe acne and hirsutism are the main findings. The scale examines nine body areas —such as the upper lip, chin, chest, abdomen, back, arms, and legs— scoring each from 0 to 4 according to the amount of terminal hair present. A total score of 4–6 or higher indicates hirsutism, which can be classified as mild (0–15), moderate (16–25), or severe (above 25).

Introduction

Diagnosis - Ultrasound

Clinical hyperandrogenism

Biochemical hyperandrogenism

Irregular cycles

Ultrasound

• When irregular menstrual cycles and hyperandrogenism are present, an ovarian ultrasound is not required for diagnosis.
• Among diagnostic parameters, the total follicle count per ovary is the most effective, followed by the follicle number per cross-section and ovarian volume as ultrasound markers in adult women.
• Ultrasound should not be used for the diagnosis of PCOS in adolescents due to the high prevalence of multifollicular ovaries at this stage of life.

Introduction

Diagnosis - Ultrasound

“Old devices”

“New devices”

Introduction

Other hormonal determinations

• LH/FSH ratio >1.
• AMH (should not be used alone).
• Insulin resistance.
• HOMA/QUICKI indices.
• Some groups recommend an oral glucose tolerance test (OGTT) when BMI >27.

In obese women, the LH/FSH ratio tends to be closer to 1, whereas in lean women it is typically higher, around 2–3.

Introduction

Differential diagnosis

• Hyperthecosis.
• Nonclassical congenital adrenal hyperplasia.
• Cushing syndrome.
• Thyroid dysfunction.
• Androgen-secretory ovarian and adrenal tumors.
• Acromegalia.
• Hyperprolactinemia.

Pathology

Alteration of the HYPOTHALAMIC–PITUITARY–OVARIAN axis

Functional ovarian hyperandrogenism

GnRH hyperpulsatility ↑ Androgens (derived from the 5 alpha reductase).

• Follicular atresia.
• Decrease in follicular selection with anovulation.
• Decreased progesterone.

Pathology - no audio

Hyperandrogenism

Genetic factors

Environmental factors

EXCESS ANDROGENS

ADIPOCYTES

• Decreased adiponectin: IR.

• Insulin activates AKR1C3 in adipose tissue, increasing androgen secretion.

OVARYIncreased growth of small preantral follicles, with subsequent arrest: polycystic morphology. Chronic anovulation.

HYPOTHALAMIC–PITUITARY AXISIncreased LH:FSH ratioIncreased LH pulse frequency/amplitudeRelative decrease in FSH

INSULIN RESISTANCE (IR) / HYPERINSULINISMInsulin: Synergy with LH: increases androgen production by theca cells. Decreases hepatic synthesis of SHBG (sex hormone–binding globulin). Increases ovarian activity of enzymes P450c17 and P450scc: enhances androgenic steroidogenesis.

Pathology

Theca

Granulosa

Androstendione

Testosterone

Estradiol

Estrone

Clinical implications

• Metabolic disorders
• Infertility problems

Clinical implications

Metabolic disorders

• Infertility
• Endometrial cancer

Gynecological

• Obesity
• Isulin resistance

• DM2
• Dyslipidemia
• Hypertension
• Hepatic steatosic
• Sleep apnea

Metabolic

• Gestational diabetes
• Preterm labor
• Gestational hypertension
• Preeclampsia
• Delivery by cesarean section

Obstetric

Dunaif, et al., 1989

Clinical implications

• Depression
• Anxiety
• Feeding disorders

Other

• Admission to neonatal ICU
• Perinatal mortality
• Preterm labor

Fetal risks

Dunaif, et al., 1989

Clinical implications

Sterility

Anovulation

• Approximately 60% of PCOS suffer anovulation.
• Women with PCOS are not completely infertile. Spontaneous ovulation: 32%.

Alteration in oocyte competence (hyperandrogenism and hyperinsulinemia). Higher miscarriage rate.

Potential causes of the increased risk in pregnancy complications in women with PCOS. All factors shown in the figure can increase the risk of obstetric/neonatal complications directly and/or through an altered trophoblast invasion and placentation. PCOM, polycystic ovarian morphology.

Sterility

Lifestyle modifications

Ovulation induction

Letrozole / Clomiphene citrate Insulin sensitizers Gonadotropins or ovarian drilling

Assisted reproduction techniques

Sterility

Obesity - Lifestyle modifications

• The lifestyle modification will be the fist option when the BMI is >28.

• Restores ovulation and favors pregnancy.
• Decreases miscarriage rate.
• Improves insulin resistance.
• Prevents long-term effects associated with PCOS.

• Weight loss may restore associated hormone alterations.
• A 5-10% weight loss may be enough to restore the ovarian function and improve the response to the treatment.

Dunaif, et al., 1989

Sterility

Lifestyle modifications

Treatment is multifactorial:

• A calorie-restricted diet of 1,500–2,000 kcal. There is no ideal diet, but certain recommendations apply:
• A balanced diet with 50% carbohydrates, 20% fats, and 30% proteins.

• Regular exercise 3–5 days per week (150–300 minutes weekly).
• Behavioral modifications.
• Medical treatment: orlistat, sibutramine, semaglutide (GLP-1).
• Surgical treatment.

The treatment of obesity is multifactorial and includes lifestyle changes, exercise, diet, pharmacological therapy, and, in some cases, bariatric surgery. However, in obese women with P C O S, there are not enough randomized studies to establish the best approach. Generally, combining pharmacological therapies with lifestyle modification yields the best results. These interventions should be implemented before initiating fertility treatment, not concurrently with assisted reproduction procedures, until the risks and benefits of such treatments are better understood.

Dunaif, et al., 1989

Sterility

Ovulation induction

• LEAN PCOS
• OBESE PCOS (who haven’t achieved a pregnancy/ovulation after the lifestyle modification)

**Direct action on the hypothalamic–pituitary axis

• Antiestrogens
• Aromatase inhibitors
• Clomiphene
• Gonadotropins
• Insulin-sensitizing agents when indicated

Indicactions

Objetive

Achieve the formation and ovulation of a single follicle.

Between 55% and 75% of patients with P C O S are infertile due to chronic anovulation. Ovulation induction is the first step in lean P C O S women who are not insulin-resistant and in obese P C O S women who have not achieved pregnancy or ovulation after a diet and exercise program. The goal of ovulation induction in women with P C O S is to achieve the development and ovulation of a single follicle. Ovulation induction can be achieved through two mechanisms: direct action on the hypothalamic–pituitary axis or by administering exogenous gonadotropins that act directly on the ovary.

Sterility

Ovulation induction - Aromatase inhibitors

Sterility

Ovulation induction - Aromatase inhibitors

Sterility

Ovulation induction - Clomiphene citrate

Sterility

Ovulation induction - Clomiphene citrate

Sterility

Ovulation induction - Clomiphene citrate

Adverse effects:

• Hypoestrogenism.

• Cervical mucus.

• Endometrium.

• Vasomotor alterations.

• Multiple gestations.

Sterility

Ovulation induction - Metformin

• Oral hypoglycemic of the biguanide group.
• Used in insulin-independent diabetes.
• Reduces glucose levels in diabetic patients.
• Does not cause hypoglycemia in normoglycemic patients.

• Improves insulin concentrations
• Improves insulin sensitivity
• Improves hyperandrogenism
• ↓ LH
• ↑ SHBG concentrations

Sterility

Ovulation induction - Gonadotropins

• Requieres ultrasound and laboratory monitoring
• More expensive
• Higher risk of OHS and multiple pregnancy

Sterility - no audio

Ovulation induction - Gonadotropins

Scheme of Ovulation Induction Protocol with GonadotropinsRegimen: Gradual increase. Starting day: 2nd–5th day of the menstrual cycle (spontaneous or after withdrawal). Initial dose: 37.5–50 IU Dose adjustment:

• From the beginning of the cycle to day 14 of stimulation, and then every 7 days.
• Increase by 50% of the previous dose.
• The maximum recommended daily dose is 225 IU.
• The dose is progressively reduced if excessive follicular growth is observed.
• Initial dose in subsequent cycles: will depend on the effective dose from the previous cycle (if the effective dose was the initial one, start with the same; if it was higher, start with the immediately lower dose than the effective one).

Monitoring: Transvaginal ultrasound, initially every 4–7 days if there is no response, and every 2–3 days when the follicle reaches >12 mm in diameter. Ovulation trigger: hCG (250 µg hCG-r). Cycle cancellation:

• Due to hyperresponse if more than two follicles ≥16 mm and two additional follicles ≥14 mm.
• Due to hyporesponse in the absence of response after 45 days of stimulation.

Sterility

Ovulation induction - Ovarian drilling

PÁG. 16

Live birth rates are the same as those of GT (ovulations, pregnancies and LBR).

Advantages

Disadvantages

Sterility

Ovulation induction - D-chiro-inositol / Myo-inositol?

• Meta-analysis is not possible due to a lack of RCTs with an adequate size.
• Not enough evidence on an improvement of metabolic parameters or reproductive hormones.
• Small evidence of an improvement in ovulation.
• Effect on the reproductive outcome in PCOS?

Sterility - no audio

Ovulation induction

The issue is that in Spain, for example, there is no approved indication for the use of letrozole in premenopausal women, due to a Canadian study that reported an increased incidence of congenital cardiac and musculoskeletal anomalies.

Sterility - no audio

Ovulation induction

Letrozole shows a higher probability of pregnancy and live birth.

Sterility - no audio

Ovulation induction

Clinical pregnancy and live birth rates — Letrozole > Clomiphene.

Sterility - no audio

Ovulation induction

• Pharmacological treatments are more effective than placebo or no intervention in achieving ovulation and pregnancy.
• Clomiphene + metformin and letrozole > clomiphene alone in terms of ovulation and pregnancy rates.
• Letrozole > clomiphene for live birth rate.
• Letrozole and metformin are associated with a lower risk of multiple pregnancy compared to clomiphene.

Sterility - no audio

Sterility

IVF

Should we force it with ICSI?

No. I don´t think its necessary.

Sterility - no audio

IVF

Sterility

IVF

The GnRH antagonist protocol yields similar results to the GnRH agonist cycle in terms of outcomes.

The long GnRH cycle is the most widely used protocol in patients with P C O S. It involves administering a GnRH analogue from the mid-luteal phase of the cycle preceding stimulation. This produces pituitary desensitization, leading to suppression of endogenous gonadotropins and, consequently, ovarian steroids. In principle, this provides more favorable conditions for controlling stimulation. At IVI, we usually administer a combined oral contraceptive starting on the first day of menstruation in the cycle prior to stimulation, and begin GnRH agonist administration from the 16th combined oral contraceptive tablet onward. Due to the particular ovarian response in P C O S patients, the appropriate gonadotropin doses are lower than those required in patients with normal ovarian characteristics. It is recommended to start stimulation with low individualized gonadotropin doses (150 international units per day for patients with BMI <30 and 225 international units per day for BMI >30). Frequent follicular monitoring should be performed using vaginal ultrasound and serum estradiol measurements, and the dose should be adjusted subtly if necessary (by 37.5 to 75 international units per day). GnRH antagonists have also been introduced into the therapeutic arsenal. Due to their mechanism of action —competitive inhibition of the pituitary GnRH receptor— they produce an immediate and profound suppression of LH secretion, making them a valid alternative to GnRH agonists for controlling ovarian stimulation in these patients. There are two types of GnRH antagonist protocols: Single-dose protocol, where a 3 mg dose of antagonist is administered when the dominant follicle reaches 14 mm in diameter. Multiple-dose protocol, which is more widely used, in which 0 point twenty five miligrams per day of antagonist is administered, generally starting from the 6th day of stimulation and continuing until hCG administration.

Sterility

IVF

...However, since ovarian hyperstimulation syndrome (OHSS) is avoided, the antagonist protocol is considered superior.

Sterility

IVF

• Different response to ovarian stimulation.
• Androgens increase FSH follicular receptors, so they have a perfect sensitivity to gonadotropins.

OBESITY

RISK OF MULTIPLE PREGNANCY

RISK OF OVARIAN HYPERSTIMULATION SYNDROME

SURGICAL RISK

Sterility

IVF

Sterility

IVF

With metformin:

• Longer stimulation period.
• Higher gonadotropin consumption.
• Fewer dominant follicles.
• Lower estradiol levels.
• More cycle cancellations due to poor response and fewer due to OHSS.
• Use in cycles with agonists?

Sterility

IVM

Conclusions - no audio

• PCOS affects 8-13% of women in their fertile age and presents diverse phenotypical expressions, with hyperandrogenism and insulin resistance comprising its physiopathological bases.

• It can lead to menstrual alterations, hirsutism, subfertility, and gestational complications in young women.

• The treatment of choice for fertility, after lifestyle therapy in obese women, is letrozole.

• IVF is indicated in cases of associated pathology or failure of ovulation induction. Special caution should be taken regarding OHSS: GnRH antagonists are preferable.
• Oocyte IVM remains to be evaluated.

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• Does not require monitoring.
• Monofollicular cycles.
• Multiple pregnancy rate similar to the general population.
• No ovarian hyperstimulation syndrome.
• Lower cost.

• Surgical risk (especially in obese women)
• Cannot be repeated
• Positive effect limited to 6 months
• Postsurgical adhesions
• Possible reduction of follicular reserve
• Possible risk of premature ovarian failure