Polycystic ovary syndrome

Description

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, with an estimated prevalence of 6-10%.  PCOS is the most common cause of anovulatory infertility (meaning infertility due to a lack of ovulation).  PCOS is classified as a syndrome because it is a heterogeneous disorder: not all women with PCOS express all the features associated with the disorder.

PCOS is diagnosed when a woman has 2 out of 3 diagnostic characteristics:

• hyperandrogenism
  Hyperandrogenism is excess secretion of androgens.  This can be measured biochemically, but also may cause clinical symptoms.  Hyperandrogenism may cause hirsutism, which is a masculine pattern of hair growth on the body, and acne, because androgens have an effect on the sebaceous glands of the skin that promotes acne. Androgens may also cause hair loss on the scalp (alopecia).
• problems with ovulation
  Problems with ovulation affect the timing of menstruation.  A woman might experience oligomenorrhea (irregular menstruation where cycles are longer than 35 days) or amenorrhea (a lack of menstruation). 
  
• polycystic ovarian morphology
  PCOS gets its name from changes in the ovary.  In polycystic ovaries, the ovaries are enlarged and contain multiple immature follicles (greater than 24 per ovary). 
  

Diagnosis also involves tests that exclude other causes of hyperandrogenism and anovulation.

There are also metabolic disturbances associated with PCOS. Frequently, women with PCOS are found to be insulin resistant. Because insulin resistance is a decreased sensitivity to insulin, this means that more insulin is necessary to achieve the same effect. For this reason, individuals who are insulin resistant have higher levels of insulin secretion or hyperinsulinemia. Because women with PCOS are insulin resistant, they are at a greater risk for developing type 2 diabetes mellitus (T2DM).  Many women with PCOS may be overweight, which can contribute to their insulin resistance and risk for T2DM.

Endocrine disturbances in PCOS

Normal follicle development begins when estrogen and progesterone levels drop due to degeneration of the corpus luteum. The release from negative feedback inhibition allows a small but steady increase in FSH and LH levels that stimulates the growth phase for a group of follicles. In the early follicular phase, granulosa cells respond to FSH only, while thecal cells respond to LH. The hormonal interactions in the early follicular phase are shown in the figure at right.

The cause of PCOS is not at all clear, but one consistent observation is that there is an imbalance in gonadotropin production. LH secretion is elevated, while FSH secretion is the same, or even decreased. LH stimulates theca cell proliferation and secretion of androgens, but there is insufficient FSH to stimulate granulosa cells. Recall that production of estrogen by the ovary requires the activity of the enzyme aromatase that is expressed in granulosa cells. The result is high levels of androgens secreted from the ovary (hyperandrogenism), and a failure of follicle development to progress.

The figure above depicts how the endocrine disturbances in PCOS become part of a vicious cycle, where the abnormalities are reinforced. The androgens secreted from the ovary are converted to estrogen because certain body tissues (in particular, adipose tissue) express aromatase. This continuous level of estrogen causes abnormal feedback regulation of gonadotropin secretion, such that LH secretion continues to be high relative to FSH secretion. Hyperinsulinemia contributes to the problem because insulin stimulates ovarian androgen production.

Treatment for PCOS in women who don't want to get pregnant

Hormonal contraceptives

If a woman is not seeking to get pregnant, PCOS is often treated with hormonal contraceptives. The goal in treatment is to decrease hyperandrogenism and to address the negative effects of PCOS on the endometrium of the uterus.

Typically, hormonal contraceptives contain a low dose of estrogen and progesterone, and are taken for 3 weeks, with one week off for a "withdrawal bleed". The estrogen and progesterone act to restore normal negative feedback regulation and lower LH secretion. This is often sufficient to reduce hyperandrogenism and its associated symptoms.

Hormonal contraceptives are also useful for preventing uterine problems. In untreated PCOS, the endometrium experiences unopposed estrogen:  that is, high levels of estrogen with no progesterone, because the cycle doesn't advance to the luteal phase. Recall that estrogen stimulates endometrial proliferation, while high levels of progesterone (as occur during the luteal phase) will stop proliferation and promote endometrial secretion.  Long stretches of unopposed estrogen will promote too much endometrial proliferation, and can cause a woman to have excessive menstrual bleeding when she does have a period.  Increased stimulation of endometrial proliferation (as occurs in PCOS) also increases a woman's risk for the development of endometrial cancer.

Treatment for PCOS in women who want to become pregnant (ovulation induction)

Letrozole

If a woman is seeking to become pregnant, the first line of therapy is treatment with letrozole.  Letrozole is an aromatase inhibitor that is approved for the treatment of breast cancer in post-menopausal women.  Letrozole is not FDA approved for ovulation induction, but it has been found to be an effective treatment, and is now the first line of treatment because of its superiority to clomiphene in rates of pregnancy and live births. Letrozole prevents the conversion of androgens to estrogens. Letrozole works to induce ovulation by limiting estrogen’s negative feedback inhibition of gonadotropin secretion.

Clomiphene

Clomiphene is an older drug, which used to be the first line of treatment for ovulation induction.  Clomiphene acts as an estrogen antagonist in the hypothalamus and anterior pituitary.  It prevents the negative feedback effect of estrogen, thus allowing FSH secretion to increase so that follicle development can be stimulated.


A potential advantage of letrozole over clomiphene is that it has a shorter half-life, allowing normal estrogen action later in the cycle. In the mid-follicular phase, negative feedback from estrogen limits gonadotropin secretion so that only a single follicle becomes dominant. Thus, ovulation induction with aromatase inhibitors should have less risk than clomiphene for inducing multiple ovulations. As well, the shorter half-life allows more estrogen stimulation of endometrial development during the proliferative phase in the uterus.

Metformin

This treatment approach addresses the problem of insulin resistance. Metformin is a treatment for type 2 diabetes mellitus that works to improve insulin sensitivity.  Studies show that in women who are insulin resistant, metformin is apparently safe and effective in lowering insulin and androgen levels, and may increase ovulation.  However metformin is not recommended as a first-line therapy for ovulation induction, because it is much less effective than letrozole or clompiphene.

Weight loss improves insulin sensitivity, and can also restore normal ovulatory cycles in some women with PCOS.

FSH

In some women, clomiphene and other treatments are not successful at inducing ovulation. In this case, exogenous FSH is needed to stimulate follicle development. The first treatment developed was menotropin, a mixture of gonadotropins purified from the urine of menopausal women. (Can you think why this would be a particularly rich source of FSH and LH?) Although menotropin contains LH, it is really the FSH that is important for stimulating ovulation in women with PCOS. Urofollitropin is FSH purified from menopausal urine. More recently, purified recombinant FSH (follitropin) has been produced.

Treatment with FSH is more expensive, and involves more risk. One problem is that high levels of FSH may induce multiple ovulations and cause higher order pregnancies (i.e. twins or triplets) which are risky for the mother and the developing fetuses. Another problem is ovarian hyperstimulation syndrome, a dangerous condition that arises when the ovary is stimulated so that multiple follicles mature. During ovarian hyperstimulation syndrome there is an increase in vascular permeability that leads to edema, nausea, and abdominal pain. If severe, it can result in clotting abnormalities, respiratory distress, and renal failure. Because of the risk of ovarian hyperstimulation, a woman treated with gonadotropins needs to be carefully monitored with transvaginal ultrasound (to monitor the number of developing follicles) and for excessive increases in estrogen secretion.