Polycystic Ovary Syndrome

Pathogenesis

A complete understanding of the underlying pathophysiology of PCOS is still lacking. Because of the heterogeneity of this disorder, there are most likely multiple underlying pathophysiologic mechanisms. Several theories have been proposed to explain the pathogenesis of PCOS.^[8] 1) An alteration in gonadotropin-releasing hormone secretion results in increased luteinizing hormone (LH) secretion. 2) An alteration in insulin secretion and insulin action results in hyperinsulinemia and insulin resistance. 3) A defect in androgen synthesis that results in increased ovarian androgen production. We will discuss each of these theories in more detail.

LH Secretion

LH hypersecretion is a characteristic hallmark of PCOS. LH is secreted in a pulsatile manner. Women with PCOS have an increase in both the LH pulse frequency and amplitude, resulting in increased 24-hour secretion. This increase in LH secretion is thought to occur as a result of increased frequency of hypothalamic gonadotropin-releasing hormone (GnRH) pulses. Increased LH, in turn, leads to an increase in androgen production by the theca cells within the ovary.^[3,8]

Hyperinsulinemia and Insulin Resistance

Insulin resistance, defined as reduced glucose response to a given amount of insulin, is a characteristic metabolic disturbance associated with PCOS. Both obese and nonobese women with PCOS have a higher incidence of insulin resistance and hyperinsulinemia than age-matched controls; however, obese women with PCOS have significantly decreased insulin sensitivity compared with nonobese women who have PCOS.

Insulin resistance is known to precede the development of type 2 diabetes mellitus. Studies have shown that 30% to 40% of women with PCOS have impaired glucose tolerance, and as many as 10% develop type 2 diabetes mellitus by the age of 40.^[3,8]

Several studies have also shown a strong correlation between insulin resistance and hyperandrogenism. This association dates back to 1921, when Achard and Thiers reported on a bearded woman who was also a diabetic.^[5] Insulin acts synergistically with LH to enhance androgen production in the ovarian theca cells. Insulin also decreases hepatic synthesis and secretion of sex hormone-binding globulin, the hormone that binds testosterone in the circulation, thus increasing the amount of free testosterone that is biologically available.^[8,9] Women with PCOS and hyperinsulinemia typically have elevated free testosterone, but the total testosterone concentration may be at the upper range of normal or only modestly elevated.^[8]

Androgen Excess

The increase in LH, together with hyperinsulinemia, leads to an increase in androgen production by ovarian theca cells.^[8] The most likely primary factor driving the increase in testosterone secretion in PCOS is an increase in ovarian enzymatic activity involved in the synthesis of testosterone precursors.^[10]

Genetics

A familial pattern in some cases suggests a genetic component, but the candidate genes have yet to be identified.^[8]

Cite this: Polycystic Ovary Syndrome - Medscape - Nov 01, 2006.

Table 1. Differential Diagnosis for PCOS
Condition	Clinical Feature	Diagnosis
Nonclassical congenital adrenal hyperplasia due to deficiency of 21-hydroxylase	Severe hirsutism, clitoromegaly, regular menses, family history, and short stature	Elevated serum 17-hydroxyprogesterone, androstenedione, and testosterone
Cushing's syndrome	Obesity, hirsutism, acne, menstrual irregularity, moonlike facies, buffalo hump, hypertension, muscle wasting, abdominal striae, and osteoporosis	Elevated 24-hour urinary free cortisol levels
Androgen-producing adrenal or ovarian neoplasms	Rapid onset of symptoms. Most common symptoms are severe hirsutism, clitoromegaly, male-pattern hair loss, acne, and lowering of the voice	Extremely elevated plasma androgen levels; tumor detected by palpation and/or ultrasound
Hyperprolactinemia	Oligomenorrhea or amenorrhea; galactorrhea	Elevated plasma prolactin level
Thyroid disorder	May have irregular menstrual cycles; may have enlarged thyroid gland	Abnormal TSH and T₃ and T₄ levels
Premature ovarian failure	Oligomenorrhea or amenorrhea; signs and symptoms of low levels of estrogen (e.g., hot flashes, vaginal dryness)	Elevated FSH levels; normal or low levels of estradiol

Sources: Chang 2004;^[1] Ehrmann 2005;^[3] The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group 2004.^[4]

Table 2. Medications That May Cause Hirsutism
Medication	Brand Name
*Antiseizure*
Phenytoin	Dilantin
Valproate	Depakote
Valproic acid	Depakene
*Corticosteroids*
Betamethasone	Celestone
Cortisone	Cortone
Dexamethasone	Decadron
Fludrocortisone	Florinef
Hydrocortisone	Cortef
Methylprednisolone	Medrol
Prednisone	Deltasone
*Anabolic Agents*
Danazol	Danocrine, Cyclomen
Testosterone	Andro 100, Androderm, Testoderm
Minoxidil	Loniten, Rogaine
*Other Medications*
Metoclopramide	Reglan
Methyldopa	Aldomet
Reserpine	Serpasil
*Phenothiazine Derivatives*	Antihistamines for treatment of allergies
Promethazine	Phenergan

From: Hill 2003;^[10] Hunter and Carek 2003.^[12]

Table 3. Signs of Virilization
Clitoromegaly
Deepening of the voice
Increased muscle mass
Loss of breast tissue
Malodorous perspiration
Temporal hair recession and balding

Sources: Hill 2003;^[10] Hunter and Carek 2003.^[12]

Table 4. Criteria for the Diagnosis* of Metabolic Syndrome in Women With PCOS
Risk Factor	Criteria
Waist circumference	35 inches (>88 cm)
Triglycerides	≥150 mg/dL
High-density lipoprotein cholesterol	<50 mg/dL
Blood pressure	≥135/ ≥85
Fasting and 2-hour glucose utilizing an oral glucose tolerance test	110-126 mg/dL and/or 2-hour glucose 140-199 mg/dL

Sources: The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group 2004;^[4] Apridonidze et al. 2005.^[14]
*Persons meeting three of the five criteria qualify for the diagnosis of the syndrome

Table 5. Pharmacologic Therapy for PCOS
Agent	Mechanism of Action	Uses	Examples
Antiandrogens	Inhibit androgens from binding to the receptors	Androgen symptoms (e.g., hirsutism, acne, oily skin)	Spironolactone (Aldactone): 50-200 mg/day Flutamide (Eulexin): 250 mg bid or tid
Biguanides	Reduces hepatic glucose production, lowering insulin levels; possible improvement in ovarian steroidogenesis	Androgen symptoms; Menstrual irregularity; Ovulation induction; Insulin resistance	Metformin (Glucophage): Initially, 500 mg bid or 850 increase from 500 mg twice daily to 850 mg twice daily maximum daily dose is 2.5 g in two or three divided doses
Clomiphene citrate (Clomid)	Antiestrogen; acts to induce rise in FSH and LH	Ovulation induction	Clomid: Start with lowest available dose (50 mg), with 50 mg increments of increased dosage if ovulation is not detected
Eflornithine HCL (Vaniqa)	Inhibition of ornithine decarboxylase	Unwanted facial hair	Vaniqa: Apply to face twice daily at least 8 hours apa
Hormonal Contraception (estrogen-progestin combination therapy)	Increases SHBG; suppresses LH and FSH; Antiandrogen	Androgen symptoms; Menstrual irregularity	Oral contraceptives; Ortho Evra Transdermal Patch; NuvaRing
Thiazolidinedione	Enhances insulin action at target tissues level	Androgen symptoms; Menstrual irregularity; Ovulation induction; Insulin resistance	Pioglitazone (Actos): Initially 15 mg or 30 mg once dosage 45 mg once daily

FSH = follicle-stimulating hormone; LH = luteinizing hormone; SHBG = sex hormone-binding globulin
Sources: Ehrmann 2005;^[3] Hill 2003;^[10] Pritts 2002;^[11] Hunter and Carek 2003;^[12] Harborne et al. 2003.^[23]

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Polycystic Ovary Syndrome

Pathogenesis

LH Secretion

Hyperinsulinemia and Insulin Resistance

Androgen Excess

Genetics

Tables

Tables

Tables

Tables

Tables

References

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