Polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS)

What is Polycystic ovary syndrome (PCOS)?

PCOS is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain etiology. Both genes and the environment contribute to PCOS. Obesity, exacerbated by poor dietary choices and physical inactivity, worsens PCOS in susceptible individuals.
PCOS produces symptoms in approximately 5% to 10% of women of reproductive age (12–45 years old). It is thought to be one of the leading causes of female subfertility and the most frequent endocrine problem in women of reproductive age.
The principal features are anovulation, resulting in irregular menstruation, amenorrhea, ovulation-related infertility, and polycystic ovaries; excessive amounts or effects of androgenic hormones, resulting in acne and hirsutism; and insulin resistance, often associated with obesity, Type 2 diabetes, and high cholesterol levels.[8] The symptoms and severity of the syndrome vary greatly among affected women.

Classification

The World Health Organization criteria for classification of anovulation include the determination of oligomenorrhea (menstrual cycle >35 days) or amenorrhea (menstrual cycle > 6 months) in combination with concentration of prolactin, follicle stimulating hormone (FSH) and estradiol. Almost 80% of anovulatory patients have normal serum FSH and estradiol levels and demonstrate very heterogeneous symptoms ranging from anovulation, obesity, biochemical or clinical hyperandrogenism and insulin resistance. PCOS is the most common cause of anovulation in women with normal serum FSH and estradiol levels. Despite the heterogeneity in symptoms associated with PCOS, the essential feature is arrested follicular development at the stage when selection of the dominant follicle should normally occur.[ In a normal menstrual cycle, one egg is released from a dominant follicle – essentially a cyst that bursts to release the egg. After ovulation the follicle remnant is transformed into a progesterone-producing corpus luteum, which shrinks and disappears after approximately 12–14 days. In PCOS, there is a so- called "follicular arrest", i.e., several follicles develop to a size of 5–7 mm, but not further. No single follicle reaches the preovulatory size (16 mm or more). The small ovarian follicles are believed to be the result of disturbed ovarian function with failed ovulation, reflected by the infrequent or absent menstruation that is typical of the condition.

Clinical signs and symptoms associated with PCOS

  • Symptom Frequency
  • Alopecia 3-6%
  • Acanthosis nigricans <1-3%
  • Infertility 20-74%
  • Elevated Serum LH 40-51%
  • Elevated testosterone 29-50%
  • Symptom Frequency
  • Oligomenorrea 29-52%
  • Amenorrea 19-51%
  • Hirsutism 64-69%
  • Obesity 35-41%
  • Acne 27-35%

Signs and symptoms

PCOS includes a heterogeneous collection of signs and symptoms with varying degree of mildness and severity in affecting the reproductive, endocrine and metabolic functions.The classic triad of the disorder includes hirsutism, menstrual dysfunction, and obesity. Some common symptoms of PCOS include:

  • Menstrual disorders: PCOS mostly produces oligomenorrhea or amenorrhea, but other types of menstrual disorders may also occur.
  • Infertility:This generally results directly from chronic anovulation (lack of ovulation).
  • Hyperandrogenism: The most common signs are acne and hirsutism (male pattern of hair growth), but it may produce hypermenorrhea (very frequent menstrual periods) or other symptoms.Approximately three-quarters of patients with PCOS (by the diagnostic criteria of NIH/NICHD 1990) have evidence of hyperandrogenemia.
  • Metabolic syndrome: This appears as a tendency towards central obesity and other symptoms associated with insulin resistance. Serum insulin, insulin resistance andhomocysteine levels are higher in women with PCOS.

When comparing success rates of different clinics, it is important to know what type of pregnancies are being compared. A chemical pregnancy is one confirmed by blood or urine tests, but in a clinical pregnancy where pregnancies are typically verfied through ultrasound, a miscarriage may occur before the pregnancy can be confirmed. After a clinical pregnancy has been verified, a miscarriage may still occur, but it is less likely.

Cause

PCOS is a complex, heterogeneous disorder of uncertain aetiology. Both genes and the environment contribute to PCOS. Obesity, exacerbated by poor dietary choices and physical inactivity, worsens PCOS in susceptible individuals. There is strong evidence that there is a genetic component in many cases. Such evidence includes the familial clustering of cases, greater concordance in monozygotic compared with dizygotic twins and heritability of endocrine and metabolic features of PCOS.
The genetic component appears to be inherited in an autosomal dominant fashion with high genetic penetrance but variable expressivity in females; this means that each child has a 50% chance of inheriting the predisposing genetic variant(s) from a parent, and if a daughter receives the variant(s), then the daughter will have the disease to some extent. The genetic variant(s) can be inherited from either the father or the mother, and can be passed along to both sons (who may be asymptomatic carriers or may have symptoms such as early baldness and/or excessive hair) and daughters, who will show signs of PCOS. The allele appears to manifest itself at least partially via heightened androgen levels secreted by ovarian follicle theca cells from women with the allele. The exact gene affected has not yet been identified.
The clinical severity of PCOS symptoms appears to be largely determined by factors such as obesity.

Pathogenesis

Polycystic ovaries develop when the ovaries are stimulated to produce excessive amounts of male hormones (androgens), particularly testosterone, by either one or a combination of the following (almost certainly combined with genetic susceptibility:

  • the release of excessive luteinizing hormone (LH) by the anterior pituitary gland[citation needed]
  • through high levels of insulin in the blood (hyperinsulinaemia) in women whose ovaries are sensitive to this stimulus
Alternatively or as well, reduced levels of sex-hormone binding globulin can result in increased free androgens.[citation needed]
The syndrome acquired its most widely used name due to the common sign on ultrasound examination of multiple (poly) ovarian cysts. These "cysts" are actually immature follicles, not cysts ("polyfollicular ovary syndrome" would have been a more accurate name). The follicles have developed from primordial follicles, but the development has stopped ("arrested") at an early antral stage due to the disturbed ovarian function. The follicles may be oriented along the ovarian periphery, appearing as a 'string of pearls' on ultrasound examination. There is also an increase in volume of ovary, especially due to increase in stroma.
Women with PCOS have higher GnRH, which in turn results in an increase in LH/FSH ratio.
A majority of patients with PCOS have insulin resistance and/or are obese. Their elevated insulin levels contribute to or cause the abnormalities seen in the hypothalamic-pituitary-ovarian axis that lead to PCOS. Hyperinsulinemia increases GnRH pulse frequency, LH over FSH dominance, increased ovarian androgen production,[13] decreased follicular maturation, and decreased SHBG binding; all these steps contribute to the development of PCOS.[citation needed] Insulin resistance is a common finding among patients of normal weight as well as overweight patients.
In many cases PCOS is characterised by a complex positive feedback loop of insulin resistance and hyperandrogenism. In most cases it can not be determined which (if any) of those two should be regarded causative. Experimental treatment with either antiandrogens or insulin sensitizing agents improves both hyperandrogenism and insulin resistance.[citation needed]
Adipose tissue possesses aromatase, an enzyme that converts androstenedione to estrone and testosterone to estradiol. The excess of adipose tissue in obese patients creates the paradox of having both excess androgens (which are responsible for hirsutism and virilization) and estrogens (which inhibits FSH via negative feedback).
PCOS may be associated with chronic inflammation, with several investigators correlating inflammatory mediators with anovulation and other PCOS symptoms.
It has previously been suggested that the excessive androgen production in PCOS could be caused by a decreased serum level of IGFBP-1, in turn increasing the level of free IGF-I which stimulates ovarian androgen production, but recent data concludes this mechanism to be unlikely.
PCOS has also been associated with a specific FMR1 sub-genotype. The research suggests that women who have heterozygous-normal/low FMR1 have polycystic-like symptoms of excessive follicle-activity and hyperactive ovarian function.
Polycystic ovary syndrome acquired its name due to the common sight (on an ultrasound examination) of multiple (poly) immature cysts (ovarian follicles - "polyfollicular ovary syndrome" would be a more accurate name). These follicles are structures (sacks of fluid) which each hold a single egg (an oocyte which is an undeveloped ovum or egg). In humans, oocytes are established in the ovary before birth. An ultrasound of the ovaries during the reproductive years usually shows, on average, 5-12 active follicles in each ovary. When more than 12-15 follicles are present, the ovary is called 'polycystic'. This itself does not cause adverse symptoms and should not be confused with PCOS.
Normal: less than or equal to 12 follicles. Borderline: 13-15 follicles. Mild: 16-30 follicles. Moderate: 30-50 follicles. Severe: more than 50 follicles, as a general guide - these women usually have Polycystic Ovarian Syndrome (PCOS), associated with infertility, increased facial hair, and a disturbance of hormone levels.
It takes a bit over a year, or 13 menstrual cycles, for a follicle to develop from dormancy up to the stage of releasing its eggs into the oviduct (the tube which carries the egg to the womb). The process requires a large group ofundeveloped follicles to grow and be progressively weaned into one dominant preovulatory follicle. The dominant follicle of the cycle is said by some to be selected from a cohort of class five follicles (when they are 2 - 5mm), others say class 7 (greater than or equal to 10mm); it requires about 20 days to develop to the ovulatory stage from class 5. The egg reaches its maximum growth when the follicle is 0.2mm but ovulation doesn't occur until the follicle is about 16 - 20mm.
Typically around 20 follicles mature each month and only a single follicle is ovulated. If a maturing follicle does not become the dominant follicle, it is reabsorbed into the ovary (ovarian follicle atresia) and takes on a different cell role. In PCOS, this reabsorption does not occur. Lower levels of a chemical that triggers atresia (caspase 3) was found in PCOS patients. Higher levels of a chemical that defends against atresia was also found (cIAP-2).