Polycystic Ovarian Syndrome answer

Polycystic Ovarian Syndrome

Polycystic ovarian syndrome (PCOS) is a common functional disorder of the ovaries in the United States. PCOS is seen in about 4–6% of premenopausal women in the United States which is associated with at least 50% of all cases of hirsutism with elevated testosterone levels. PCOS is an inherited disease which is transmitted as autosomal dominant trait. PCOS is the most common endocrine disorder of reproductive-aged women. PCOS affect all races and nationalities equally although sign and symptoms of androgen excess may vary among different ethnicities. The underlying cause of PCOS is genetic basis that is both multifactorial and polygenic is suspected.

Ovarian hyperthecosis, often considered a more severe form of PCOS, is a rare condition characterized by nests of luteinized theca cells distributed throughout the ovarian stroma. Affected women exhibit severe hyperandrogenism and may occasionally display frank virilization signs such as clitoromegaly, temporal balding, and voice deepening (Culiner, 1949). In addition, a much greater degree of insulin resistance and acanthosis nigricans typically is found (Nagamani, 1986).

The hyperandrogenic-insulin resistant-acanthosis nigricans (HAIRAN) syndrome is also uncommon and consists of marked hyperandrogenism, severe insulin resistance, and acanthosis nigricans (Barbieri, 1983). The etiology of this disorder is unclear, and HAIRAN syndrome may represent either a PCOS variant or a distinct genetic syndrome. Both ovarian hyperthecosis and HAIRAN are exaggerated phenotypes of PCOS, and their treatment mirrors that for PCOS described later in this chapter.

Menstrual dysfunction in women with PCOS may range from amenorrhea to oligomenorrhea to episodic menometrorrhagia with anemia. In many women with PCOS, amenorrhea and oligomenorrhea result from anovulation. In this setting, failed ovulation precludes progesterone production and then also progesterone withdrawal to trigger menses. Alternatively, amenorrhea may result from elevated androgen levels in those with PCOS. Specifically, androgens may counteract estrogen to produce an atrophic endometrium. It is therefore not uncommon to observe amenorrhea and a thin endometrial stripe in PCOS patients with elevated androgen levels.

In contrast to amenorrhea, women with PCOS may have heavy and unpredictable bleeding. In these women, progesterone is not produced due to anovulation, and chronic estrogen exposure results. This produces constant mitogenic stimulation of the endometrium. The instability of the thickened endometrium results in an unpredictable bleeding pattern.

Anovulation is one of the main problems in women with polycystic ovarian syndrome. PCOS is mainly caused by inappropriate secretion of the gonadotropin hormone. In normal physiological situations gonadotropin-releasing hormone (GnRH) is released in pulsatile manner which leads to production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland.

Model for the initiation and maintenance of polycystic ovarian syndrome (PCOS) is shown in the Figure 1.  Alterations in pulsatile gonadotropin-releasing hormone (GnRH) release is one of the known causes of this syndrome.

In female with PCOS the level of the luteinizing hormone (LH) is much higher compare to the level of the follicle-stimulating hormone (FSH) (LH: FSH>2). LH hormone effect the theca cells of the ovary, this stimulate leads to production of the androgen. Androgen is then converted to the estrone in adipose tissue. Estrone feedback decrease the level of the follicle-stimulating hormone (FSH). Low level of the FSH resulting in cystic degeneration of the follicles. Low FSH prevents stimulation of aromatase enzyme within the granulosa cells so the normal pathway of conversion of the androgen to the potent estrogen estradiol is disturbed in PCOS patients.

Increased intrafollicular estrone cause the negative feedback which inhibits FSH and eventually result in follicular atresia as shown in the figure 2. As mentioned above high levels of LH cause increased concentration of circulating androgen levels. This high level of androgen is contributed to abnormalities in patient lipid profiles and the development of hirsutism and acne. Increased circulating androgens can also be derived from the adrenal gland.

Figure 2, US image of Polycystic Ovarian Syndrome; multiple small cysts in ovary of a premenopausal female.

Obesity, insulin resistance and hyperglycemia are displayed in greater degrees in women with PCOS comparing to non-affected women. Reduced glucose-uptake response to a given amount of insulin is the main complication in insulin resistance patients. This decreased insulin sensitivity appears to stem from a post binding abnormality in insulin receptor-mediated signal transduction (Dunaif, 1997). Both lean and obese women with PCOS are found to be more insulin resistant.

Approximately 50% of women diagnosed with PCOS are obese, and most have polycystic ovaries present on sonography (see later). Underlying these features are numerous biochemical abnormalities that have been associated with this syndrome, including elevated circulating total testosterone, free testosterone, DHEAS, and insulin as well as decreased SHBG and an elevated LH-FSH ratio. However, these abnormalities are not present in all PCOS patients. In fact, 40% of women who present with only hirsutism have elevated totaltestosterone levels, and 30% to 70% have elevated DHEAS levels. Similarly, the evaluation of increased LH pulsatility, in association with low-normal FSH levels (LH-FSH ratio), is not a reliable diagnostic test. Although elevated LH-FSH ratios are common findings in thin women, in obese patients with PCOS, the ratio is within the normal range about half of the time. The short half-life of LH (∼20 minutes) is likely another major contributor to the inaccuracy of LH testing. Hyperinsulinemia has recently been hypothesized to play a major role in the pathogenesis of PCOS (see later). The prevalence of insulin resistance may approximate 50% to 60%, compared with 10% to 25% observed in the general population. However, insulin resistance is difficult to measure in the clinical setting. Part of the difficulty is that there is no universally agreed on definition of insulin resistance, and the laboratory tests are not standardized. Furthermore, baseline insulin levels vary depending on population and body weight. For example, up to 60% of ovulatory obese patients have demonstrated some form of insulin resistance. Nonetheless, there is good evidence that a subset of normal-weight women and obese women with PCOS have a greater degree of insulin resistance and compensatory hyperinsulinemia compared with weight-matched controls.

Both insulin and LH stimulate androgen production by the ovarian theca cell. As a result, affected ovaries secrete elevated levels of testosterone and androstenedione. Specifically, elevated free testosterone levels are noted in 70 to 80 percent of women with PCOS, and 25 to 65 percent exhibit elevated levels of DHEAS. In turn, elevated androstenedione levels contribute to an increase in estrone levels through peripheral conversion of androgens to estrogens by aromatase.

Classic presentation of a women with PCOS is an obese young woman with menstrual irregularities, infertility, hirsutism and other endocrine dysfunctions that become apparent within a few years of puberty.

Menstrual Dysfunction

In women with PCOS, menstrual dysfunction may range from amenorrhea to oligomenorrhea to episodic menometrorrhagia with associated iron-deficiency anemia. In most cases, amenorrhea and oligomenorrhea result from anovulation. Namely, without ovulation and endogenous progesterone production from the corpus luteum, a normal menstrual period is not triggered. Alternatively, amenorrhea can stem from elevated androgen levels. Specifically, androgens can counteract estrogen to produce an atrophic endometrium. Thus, with markedly elevated androgen levels, amenorrhea and a thin endometrial stripe can be seen.

Hyperandrogenism

This condition is usually manifested clinically by hirsutism, acne, and/or androgenic alopecia. Other signs such as increased muscle mass, voice deepening, and clitoromegaly may be seen in this patients although they are not typical in PCOS. Virilization reflects higher androgen levels and may require additional investigation regarding an androgen-producing tumor of the ovary or adrenal gland.

Hirsutism

In a female, hirsutism is typically defined as coarse, dark hairs distributed in a male pattern Figure 3. These specific characteristics make it possible to distinguish it from the Idiopathic hirsutism or drugs caused hirsutism.

Acne

Vulgaris is another clinical finding in adolescents. The prevalence of acne in women with PCOS is unknown, although one study found that 50 percent of adolescents with PCOS have moderate acne. In addition, androgen level elevation has been reported in 80 percent of women with severe acne, 50 percent with moderate acne, and 33 percent with mild acne. Women with moderate to severe acne have an increased prevalence (52 to 83 percent) of polycystic ovaries identified during sonographic examination.

The treatment choice for each symptom of PCOS depends on a woman’s goals and the severity of endocrine dysfunction. Thus, anovulatory women desiring pregnancy will undergo significantly different treatment than adolescents with menstrual irregularity and acne. Patients often seek treatment for a singular complaint and may see various specialists such as dermatologists, nutritionists, aestheticians, and endocrinologists prior to evaluation by a gynecologist.

For obese women with PCOS, lifestyle changes focused on diet and exercise are paramount to treatment at each stage of life. Even a modest amount of weight loss (5 percent of body weight) can result in restoration of normal ovulatory cycles in some women. This improvement results from reductions in insulin and androgen levels, the latter mediated through increases in SHBG levels (Huber-Buchholz, 1999; Kiddy, 1992; Pasquali, 1989).

The optimal diet that best improves insulin sensitivity is not known. Diets high in carbohydrates increase insulin secretion rates, whereas diets high in protein and fat lower those rates (Bass, 1993; Nuttall, 1985). However, very-high-protein diets are concerning with respect to stresses on kidney function. Moreover, they afford only short-term weight loss initially with lesser benefits over time (Legro, 1999; Skov, 1999). Thus, it appears that a well-balanced hypocaloric diet offers the most benefit in treating obese women with PCOS.

Although the use of insulin sensitizers in PCOS has not been approved by the Food and Drug Administration (FDA), they have been found to be increasingly beneficial for both metabolic and gynecologic issues. Of these agents, metformin is the most commonly prescribed, particularly in women with impaired glucose tolerance and insulin resistance. This drug improves peripheral insulin sensitivity by reducing hepatic glucose production and increasing target tissue sensitivity to insulin. Metformin decreases androgen levels in both lean and obese women, leading to increased rates of spontaneous ovulation (Batukan, 2001; Essah, 2006; Haas, 2003).

A number of studies have demonstrated that up to 40 percent of anovulatory women with PCOS will ovulate, and many will achieve pregnancy with metformin alone (Fleming, 2002;Neveu, 2007). Metformin is a category B drug and is safe to use as an ovulatory induction agent. As such, it may be used alone or in concert with other medications such asclomiphene citrate (Chap. 20). Specifically, metformin has been shown to increase the ovulatory response to clomiphene citrate in patients who were previously clomiphene resistant (Nestler, 1998). Despite these positive findings regarding metformin and ovulation induction, in a randomized prospective study of 626 women, Legro and colleagues (2007)found higher live-birth rates with clomiphene citrate alone (22 percent) than with metforminalone (7 percent).

A rare adverse side effect of metformin is lactic acidosis, which is almost exclusively found in patients with renal insufficiency, liver disease, or congestive heart failure. More common side effects are gastrointestinal, and these can be minimized by starting at a low dose and gradually increasing the dose over several weeks to an optimal level. In clinical studies, 1500 to 2000 mg in divided doses daily with meals is typically used.

The thiazolidinediones, also known as glitazones, are another class of medications used for patients with diabetes mellitus and include rosiglitazone (Avandia) and pioglitazone (Actos). These agents bind to insulin receptors on cells throughout the body, causing them to become more responsive to insulin and thereby lowering serum glucose and insulin levels. Similar to metformin, rosiglitazone and pioglitazone have been shown to improve ovulation in some patients (Azziz, 2001; Dunaif, 1996b; Ehrmann, 1997). However, the glitazones are category C drugs and thus should be used as ovulation induction agents in rare cases and discontinued once pregnancy is achieved.

With hirsutism treatment, a primary goal is lowering androgen levels to decrease the hair growth. However, medical therapies will not eliminate hair already present. Moreover, treatments may require 6 to 12 months before clinical improvement is apparent. For this reason, clinicians should be familiar with temporary hair removal methods that may be used in the interim. Permanent cosmetic therapies can then be implemented once medications have reached maximal therapeutic effect.

Several options are available to decrease androgen levels affecting hair follicles. First, as described earlier, COCs are effective in establishing regular menses and lowering ovarian androgen production. Second, GnRH agonists lower gonadotropin levels over time, and in turn subsequently lower androgen levels. Despite their effectiveness in treating hirsutism, long-term administration of GnRH agonists is not ideal due to associated bone loss, high cost, and menopausal side effects. Last, 5α-reductase inhibitors block conversion of testosterone to DHT. Of these, finasteride is available as a 5-mg tablet for prostate cancer (Proscar) and a 1-mg tablet for the treatment of male alopecia (Propecia). Most studies have used 5-mg daily doses for women and have found finasteride to be modestly effective for hirsutism treatment (Fruzzetti, 1994;Moghetti, 1994). Side effects are low with finasteride, although decreased libido has been noted. However, as with other antiandrogens, the risk of male fetal teratogenicity is present, and effective contraception must be used concurrently.

Eflornithine Hydrochloride antimetabolite topical cream is applied twice daily to affected areas and is an irreversible inhibitor of ornithine decarboxylase. This enzyme is necessary for hair follicle cell division and function, and its inhibition results in slower hair growth. It does not permanently remove hair, and thus women must continue routine methods of hair removal while using this medicine.

Eflornithine hydrochloride (Vaniqa) may require 4 to 8 weeks of use before changes are noticed. However, approximately one third of patients have marked improvement after 24 weeks of eflornithine use compared with placebo, and 58 percent showed some overall improvement in hirsutism scores (Balfour, 2001).

Hair removal in hirsutism is often treated by mechanical means, and these include both depilation and epilation techniques. In addition to hair removal, lightening hair color with bleach is a cosmetic option.

Depilation describes hair removal above the skin surface. Shaving is the most common form and does not exacerbate hirsutism, contrary to the myth that it will increase hair follicle density. Alternatively, topical chemical depilatories are also effective. Available in gel, cream, lotion, aerosol, and roll-on forms, these agents contain calcium thioglycolate. This agent breaks disulfide bonds between hair protein chains, causing hair to break down and separate easily from the skin surface.

Epilation removes the entire hair shaft and root and includes techniques such as plucking, waxing, threading, electrolysis, and laser treatment. Threading, also known as “khite” in Arabic, is a fast method for removing entire hairs and is commonly used in the Middle East and India. Hairs are snared within an outstretched strand of twisted cotton thread and pulled out.

Although waxing and plucking allow effective temporary hair removal, permanent epilation may be achieved with thermal destruction of the hair follicle. Electrolysis, performed by a trained individual, involves placement of a fine electrode and passage of electric current to destroy individual follicles. It requires repetitive treatments over several weeks to months, can be painful, and can result in scarring.

Alternatively, laser therapy directs specific laser wavelengths to also permanently destroy follicles. During this process, termed selective photothermolysis, only target tissues absorb laser light and are heated. Surrounding tissues fail to absorb the selective wavelength and receive minimal thermal damage. For this reason, light-skinned women with dark hairs are better candidates for laser treatment due to the selective wavelength absorption by their hair. Advantageously, laser treatment can cover a wider surface area than electrolysis and therefore requires fewer treatments. It causes less pain, but is expensive and can result in dyspigmentation.

Prior to any epilation technique, topical anesthetics may be prescribed. Specifically, a topical cream combination of 2.5-percent lidocaine and 2.5-percent prilocaine (EMLA cream) can be applied as a thick layer that remains for 1 hour and is removed just prior to epilation. Recommended adult dosing is 1.5 g for each 2 × 2-inch area of skin treated.

Reference

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