HYPERANDROGENISM, HYPERANDROGENISM, HIRSUTISM AND POLYCYSTIC HIRSUTISM AND POLYCYSTIC

OVARY SYNDROMEOVARY SYNDROME

hyperandrogenism is any clinical or laboratory hyperandrogenism is any clinical or laboratory evidence of androgen excess in women. The evidence of androgen excess in women. The most common clinical presentation of most common clinical presentation of hyperandrogenism in reproductive-aged women hyperandrogenism in reproductive-aged women is hirsutism or acne with or without evidence of is hirsutism or acne with or without evidence of anovulation such as oligoamenorrhea - or anovulation such as oligoamenorrhea - or amenorrhea or dysfunctional uterine bleeding. amenorrhea or dysfunctional uterine bleeding. Elevated blood levels of androgens without Elevated blood levels of androgens without clinical symptoms is referred to as cryptic clinical symptoms is referred to as cryptic hyperandrogenism. hyperandrogenism.

HirsutismHirsutism refers to the presence of course refers to the presence of course terminal hairs in androgen-dependent areas on terminal hairs in androgen-dependent areas on the face and body in women.the face and body in women.

hypertrichosis, which is excessive growth of thin hypertrichosis, which is excessive growth of thin vellus hair at any body site. Hypertrichosis is vellus hair at any body site. Hypertrichosis is usually familial or associated with endocrine usually familial or associated with endocrine disturbances such as anorexia nervosa or disturbances such as anorexia nervosa or thyroid dysfunction, or with medications such as thyroid dysfunction, or with medications such as phenytoin, minoxidil or cyclosporin ).phenytoin, minoxidil or cyclosporin ).

Hirsutism affects between 2-10% of women Hirsutism affects between 2-10% of women between the ages of 18 and 45. It is often a between the ages of 18 and 45. It is often a source of psychological discomfort and may be source of psychological discomfort and may be a sign of a significant medical disorder as will a sign of a significant medical disorder as will be discussed. be discussed.

causescauses

The causes of hyperandrogenism in The causes of hyperandrogenism in reproductive aged women can be divided reproductive aged women can be divided into five categories in descending order of into five categories in descending order of prevalence. prevalence.

. Causes of Hyperandrogenism. Causes of Hyperandrogenism CommonCommon Polycystic Ovary Syndrome 80%Polycystic Ovary Syndrome 80% Idiopathic Hirsutism 15%Idiopathic Hirsutism 15% UncommonUncommon Late-Onset 21-Hydroxylase Deficiency1- 5%Late-Onset 21-Hydroxylase Deficiency1- 5% RareRare < 1% < 1% Steroidogenic Enzyme DeficienciesSteroidogenic Enzyme Deficiencies 3b-hydroxysteroid dehydrogenase3b-hydroxysteroid dehydrogenase 17-ketosteroid reductase17-ketosteroid reductase aromatasenaromatasen Androgen Secreting Tumors of Ovary or AdrenalAndrogen Secreting Tumors of Ovary or Adrenal Ovarian Hyperthecosis (a PCOS variant)Ovarian Hyperthecosis (a PCOS variant) Other EndocrineOther Endocrine HyperprolactinemiaHyperprolactinemia Cushing syndromeCushing syndrome Defects in cortisol metabolismDefects in cortisol metabolism AcromegalyAcromegaly

Idiopathic HirsutismIdiopathic Hirsutism Idiopathic hirsutism is excess terminal hair Idiopathic hirsutism is excess terminal hair

production in androgen dependent areas in the production in androgen dependent areas in the presence of regular ovulation and normal presence of regular ovulation and normal androgen levels It is the second most common androgen levels It is the second most common cause of hirsutism after PCOS and occurs in about cause of hirsutism after PCOS and occurs in about 15% of hirsute women.15% of hirsute women.

The pathophysiology of this disorder still needs to The pathophysiology of this disorder still needs to be fully elucidated, but is thought to be secondary be fully elucidated, but is thought to be secondary to increased 5a-reductase activity in the skin or its to increased 5a-reductase activity in the skin or its appendages, to other alterations in androgen appendages, to other alterations in androgen metabolism or to increased sensitivity of the metabolism or to increased sensitivity of the androgen receptor androgen receptor

Polycystic Ovary SyndromePolycystic Ovary Syndrome

PCOS is the most common cause of hirsutism PCOS is the most common cause of hirsutism and the most common endocrinopathy in and the most common endocrinopathy in reproductive aged women. It has a reproductive aged women. It has a prevalence of about 5% in Caucasian and prevalence of about 5% in Caucasian and African Americans and in European African Americans and in European populations (8-10 %). populations (8-10 %).

Adrenal and Ovarian Adrenal and Ovarian Steroidogenic Enzyme Steroidogenic Enzyme

DeficienciesDeficiencies Adrenal or ovarian steroidogenic enzyme Adrenal or ovarian steroidogenic enzyme

deficiencies are the most common cause of deficiencies are the most common cause of hyperandrogenism in post-menarcheal hyperandrogenism in post-menarcheal women after PCOS and idiopathic hirsutism. women after PCOS and idiopathic hirsutism. Nevertheless these conditions are Nevertheless these conditions are uncommon to very rare. Late-onset 21-uncommon to very rare. Late-onset 21-hydroxylase deficiency occurs in 1-5% of hydroxylase deficiency occurs in 1-5% of hirsute women, with the greatest prevalence hirsute women, with the greatest prevalence in women of Askenazi Jewish descent in women of Askenazi Jewish descent

Ovarian and Adrenal TumorsOvarian and Adrenal Tumors Both adrenal adenoma and carcinoma may Both adrenal adenoma and carcinoma may

present with virilization and present with virilization and hyperandrogenemia . hyperandrogenemia .

Androgen secreting ovarian tumors include Androgen secreting ovarian tumors include Sertoli-Leydig cell tumors, Leydig cell tumors, Sertoli-Leydig cell tumors, Leydig cell tumors, lipoid or lipid cell tumors and granulose-theca lipoid or lipid cell tumors and granulose-theca cell tumors cell tumors

Typically women with androgen secreting tumors Typically women with androgen secreting tumors have abrupt onset of symptoms distinct from have abrupt onset of symptoms distinct from menarche and a more rapid progressions of menarche and a more rapid progressions of symptoms compared to PCOS. Signs of symptoms compared to PCOS. Signs of virilization such as clitoromegaly, frontal balding virilization such as clitoromegaly, frontal balding and deepening of the voice are also more and deepening of the voice are also more common. Testosterone levels are usually common. Testosterone levels are usually greater than 200 ng/dl or 2 1/2 times the upper greater than 200 ng/dl or 2 1/2 times the upper limit of normal, but there is clearly overlap limit of normal, but there is clearly overlap between testosterone levels found in tumors between testosterone levels found in tumors and those seen in severe cases of PCOS or and those seen in severe cases of PCOS or hyperthecosis, hyperthecosis,

If a tumor is suspected, both ovarian ultrasound If a tumor is suspected, both ovarian ultrasound and adrenal CT scan should be done to and adrenal CT scan should be done to localize itlocalize it

Other Endocrine DisordersOther Endocrine Disorders Cushing syndrome and acromegaly. However Cushing syndrome and acromegaly. However

hirsutism is usually not the primary complaint hirsutism is usually not the primary complaint in these disorders. Prolactin should be in these disorders. Prolactin should be determined in all patients with anovulation. determined in all patients with anovulation.

Cushing syndrome can be ruled out by a Cushing syndrome can be ruled out by a normal 24 hour urinary cortisol or normal normal 24 hour urinary cortisol or normal overnight dexamethasone suppression test . If overnight dexamethasone suppression test . If there is any suspicion of acromegaly, a there is any suspicion of acromegaly, a somatomedin-C level (IGF-I) and/or growth somatomedin-C level (IGF-I) and/or growth hormone suppression test should be done. hormone suppression test should be done.

POLYCYSTIC OVARY SYNDROMEPOLYCYSTIC OVARY SYNDROME

PCOS is the most common endocrinopathy in PCOS is the most common endocrinopathy in women and is the most common cause of women and is the most common cause of androgen excess, affecting about 5% of androgen excess, affecting about 5% of reproductive aged women. Although reproductive aged women. Although androgen excess in women has been androgen excess in women has been recognized since the time of Hippocrates recognized since the time of Hippocrates and had been described in association with and had been described in association with diabetes in the nineteenth century diabetes in the nineteenth century

Pathophysiology of Polycystic Ovary Pathophysiology of Polycystic Ovary SyndromeSyndrome

PCOS is a complex, heterogeneous PCOS is a complex, heterogeneous disorder. It is likely genetic, environmental disorder. It is likely genetic, environmental factors contribute to its pathophysiology, factors contribute to its pathophysiology, and that no single gene mutation will be and that no single gene mutation will be found that is both necessary and sufficient found that is both necessary and sufficient to cause PCOS. The familial clustering that to cause PCOS. The familial clustering that occurs in PCOS is consistent with a genetic occurs in PCOS is consistent with a genetic susceptibility. About 50% of sisters of susceptibility. About 50% of sisters of PCOS probands have hyperandrogenemia PCOS probands have hyperandrogenemia with or without anovulation, which suggests with or without anovulation, which suggests an autosomal dominant inheritance for a an autosomal dominant inheritance for a factor predisposing to ovarian factor predisposing to ovarian hyperandrogenism hyperandrogenism

Rotterdam Criteria (2 out of 3)Rotterdam Criteria (2 out of 3)– Menstrual irregularity due to anovulation oligo-Menstrual irregularity due to anovulation oligo-

ovulationovulation– Evidence of clinical or biochemical Evidence of clinical or biochemical

hyperandrogenismhyperandrogenism– Polycystic ovaries by USPolycystic ovaries by US

presence of 12 or more follicles in each ovary presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased measuring 2 to 9 mm in diameter and/or increased ovarian volumeovarian volume

The etiology of anovulation in PCOS is often The etiology of anovulation in PCOS is often explained by high intraovarian androgen explained by high intraovarian androgen levels which induce atresia and prevent the levels which induce atresia and prevent the emergence of a dominant follicleemergence of a dominant follicle

The ovarian hyperandrogenism of PCOS is The ovarian hyperandrogenism of PCOS is gonadotropin dependent, and gonadotropin gonadotropin dependent, and gonadotropin suppression with sex steroid or GnRHa results in suppression with sex steroid or GnRHa results in normal androgen levels . It has been reported normal androgen levels . It has been reported that 75% of women with clinical evidence of that 75% of women with clinical evidence of PCOS have an elevated LH level and 94% have PCOS have an elevated LH level and 94% have an increased LH/FSH ratio . These gonadotropin an increased LH/FSH ratio . These gonadotropin secretory abnormalities have been thought to secretory abnormalities have been thought to play an important role in the development of the play an important role in the development of the ovarian hyperandrogenism characteristic of ovarian hyperandrogenism characteristic of PCOS PCOS

USUS 25% of normal ovulating women would have 25% of normal ovulating women would have

polycystic-appearing ovariespolycystic-appearing ovaries Ovaries will have a typical appearance of Ovaries will have a typical appearance of

enlarged subcapsular small follicles(<10 mm )enlarged subcapsular small follicles(<10 mm ) The ovarian volume in women with PCOS is The ovarian volume in women with PCOS is

>10 cm3 &the normal range is 4.7 -5.2 cm3>10 cm3 &the normal range is 4.7 -5.2 cm3

Treatment of Polycystic Ovary SyndromeTreatment of Polycystic Ovary Syndrome

As PCOS is found in a large proportion of the femalepopulation, treatment is only required for the patient'ssymptoms.1- AmenorrhoeaEither induce ovulation which will result in regularmenstruation (see below), or protect the endometriumagainst the effects of unopposed oestrogen stimulation by:• using the oral contraceptive pill which will result inregular menses• giving progestogens three or four times per year to induceendometrial shedding.

If a patient has been anovulatory for more If a patient has been anovulatory for more than a year, an endometrial biopsy is than a year, an endometrial biopsy is recommended before instituting therapy. recommended before instituting therapy. The oral contraceptive pill (OCP) is an The oral contraceptive pill (OCP) is an excellent choice, as it both inhibits excellent choice, as it both inhibits endometrial proliferation and reduces endometrial proliferation and reduces ovarian androgen production, thus ovarian androgen production, thus ameliorating the consequences of ameliorating the consequences of hyperandrogenism hyperandrogenism

Insulin-sensitizing drugs may also decrease Insulin-sensitizing drugs may also decrease the risk of endometrial cancer in PCOS by the risk of endometrial cancer in PCOS by lowering insulin levels and increasing the lowering insulin levels and increasing the frequency of ovulation frequency of ovulation

Although a moderate degree of insulin Although a moderate degree of insulin resistance and hyperinsulinemia is neither resistance and hyperinsulinemia is neither necessary nor sufficient to cause PCOS, it necessary nor sufficient to cause PCOS, it plays an important role in the pathogenesis plays an important role in the pathogenesis of ovarian hyperandrogenism in many cases of ovarian hyperandrogenism in many cases of PCOS. Both in vitro and in vivo evidence of PCOS. Both in vitro and in vivo evidence suggests that hyperinsulinemia contributes suggests that hyperinsulinemia contributes to excessive ovarian androgen production in to excessive ovarian androgen production in PCOS. PCOS.

2-ObesityWeight reduction has many benefits for the patient but usually proves very difficult. Once considerably overweight,patients become less active and their basal metabolic rate (BMR) is reduced, thus they require less calories to maintain their body weight.

3-Treatment of Hirsutism3-Treatment of Hirsutism Medical TherapyMedical Therapy

The aim of medical therapy is to suppress The aim of medical therapy is to suppress androgen production, block androgen androgen production, block androgen receptors or decrease the conversion of receptors or decrease the conversion of testosterone to dihydrotestosterone by testosterone to dihydrotestosterone by inhibition of the enzyme 5a-reductase inhibition of the enzyme 5a-reductase

Medical treatment of HirsutismMedical treatment of Hirsutism

Oral Contraceptive Pills - OCPs have commonly Oral Contraceptive Pills - OCPs have commonly been used to treat patients with hirsutism and been used to treat patients with hirsutism and other signs of androgen excess. The other signs of androgen excess. The progestational component of the OCP inhibits progestational component of the OCP inhibits pituitary secretion of LH, which in turn decreases pituitary secretion of LH, which in turn decreases ovarian androgen production. Progestins also ovarian androgen production. Progestins also decrease adrenal DHEAS production, possibly via decrease adrenal DHEAS production, possibly via a negative feedback loop through the a negative feedback loop through the glucocorticoid receptor . In addition, the estrogen glucocorticoid receptor . In addition, the estrogen component of oral contraceptive pills increases component of oral contraceptive pills increases production of SHBG thus decreasing the amount production of SHBG thus decreasing the amount of free testosterone available . All formulations of of free testosterone available . All formulations of low dose (≤ 0.35mg ethinyl estradiol) oral low dose (≤ 0.35mg ethinyl estradiol) oral contraceptive pills available today, contraceptive pills available today,

Androgen Receptor Antagonists – Androgen Receptor Antagonists –

cyproterone acetate was the first androgen cyproterone acetate was the first androgen receptor antagonist to be used clinically and is receptor antagonist to be used clinically and is still widely used in Europe . It is a competitive still widely used in Europe . It is a competitive inhibitor of testosterone and inhibitor of testosterone and dihydrotestosterone receptor binding and also dihydrotestosterone receptor binding and also has progestational and weak glucocorticoid has progestational and weak glucocorticoid properties . It is an effective and well-tolerated properties . It is an effective and well-tolerated treatment for hirsutism. treatment for hirsutism.

Spironolactone is a competitive inhibitor of the Spironolactone is a competitive inhibitor of the aldosterone receptor and was initially utilized as a aldosterone receptor and was initially utilized as a potassium sparing diuretic. It was soon discovered potassium sparing diuretic. It was soon discovered to have antiandrogenic properties, and when used to have antiandrogenic properties, and when used together with the OCP, it is the first line treatment together with the OCP, it is the first line treatment for hirsutism in the United States. Its antiandrogenic for hirsutism in the United States. Its antiandrogenic effects come from several mechanisms, the most effects come from several mechanisms, the most important of which is the blockade of androgen important of which is the blockade of androgen receptors in the hair follicle . In addition receptors in the hair follicle . In addition spironolactone also inhibits androgen biosynthesis spironolactone also inhibits androgen biosynthesis through the cytochrome p450 system and directly through the cytochrome p450 system and directly inhibits 5a-reductase activity. Treatment with inhibits 5a-reductase activity. Treatment with spironolactone should begin at a dose of 200 mg/d spironolactone should begin at a dose of 200 mg/d for at least 3-6 months for at least 3-6 months

Treatment with spironolactone is generally Treatment with spironolactone is generally very well tolerated with the most common very well tolerated with the most common side effects being irregular vaginal bleeding, side effects being irregular vaginal bleeding, polyuria and fatigue . It is important to polyuria and fatigue . It is important to remember that with spironolactone, as with remember that with spironolactone, as with all antiandrogens, pregnancy can still occur all antiandrogens, pregnancy can still occur with the theoretical potential for feminization with the theoretical potential for feminization of male fetuses. For that reason the OCP is of male fetuses. For that reason the OCP is often used in conjunction with often used in conjunction with spironolactone. Not only will it protect spironolactone. Not only will it protect against pregnancy, but also control against pregnancy, but also control abnormal uterine bleeding and possibly abnormal uterine bleeding and possibly potentiate the effect of spironolactone . potentiate the effect of spironolactone .

Flutamide is a nonsteroidal antiandrogen that appears Flutamide is a nonsteroidal antiandrogen that appears to work only at the androgen receptor to work only at the androgen receptor

. Flutamide 250 mg/d for six months is effective in . Flutamide 250 mg/d for six months is effective in treating hirsutismtreating hirsutism

most common side effects of flutamide are mild and most common side effects of flutamide are mild and include dry skin and increased appetite. However, include dry skin and increased appetite. However, the potential exists for a rare but severe drug-the potential exists for a rare but severe drug-induced hepatitis which limits the usefulness of this induced hepatitis which limits the usefulness of this medication . Because of this potentially severe side medication . Because of this potentially severe side effect, it is generally recommended that flutamide be effect, it is generally recommended that flutamide be utilized after other therapies have failed and that utilized after other therapies have failed and that liver transaminases are monitored appropriately. liver transaminases are monitored appropriately.

5a-reductase Inhibitors - Finasteride is a 5a-reductase Inhibitors - Finasteride is a potent inhibitor of 5a-reductase and thus potent inhibitor of 5a-reductase and thus reduces the conversion of testosterone to reduces the conversion of testosterone to its active metabolite dihydrotestosterone its active metabolite dihydrotestosterone Finasteride is well tolerated with minimal Finasteride is well tolerated with minimal side effects at the standard dose of 5 side effects at the standard dose of 5 mg/day.mg/day.

Insulin Sensitizing Agents Insulin Sensitizing Agents

*Metformin has been shown to decrease the *Metformin has been shown to decrease the objective hair growth rate by about 15% in objective hair growth rate by about 15% in women with PCOSwomen with PCOS

*troglitazone *troglitazone

* Eflornithine HCL * Eflornithine HCL

Gonadotropin Releasing Hormone Agonists - Gonadotropin Releasing Hormone Agonists - Administration of a long-acting gonadotropin Administration of a long-acting gonadotropin GnRHa such as leuprolide acetate GnRHa such as leuprolide acetate suppresses ovarian androgen production by suppresses ovarian androgen production by inhibiting pituitary gonadotropin secretion. inhibiting pituitary gonadotropin secretion. This results in decreased levels of circulating This results in decreased levels of circulating testosterone and androstenedione with no testosterone and androstenedione with no effect on adrenal androgens effect on adrenal androgens

Non-Medical Therapy Non-Medical Therapy

Epilation - Epilation includes plucking and waxing Epilation - Epilation includes plucking and waxing and involves removal of the hair from the bulb. It and involves removal of the hair from the bulb. It does not change the rate or duration of hair growth does not change the rate or duration of hair growth but repeated plucking may lead to a delay in the but repeated plucking may lead to a delay in the return to anagen and thinner hair secondary to return to anagen and thinner hair secondary to permanent matrix damage . Epilation is an permanent matrix damage . Epilation is an acceptable means of hair removal. Again it is only acceptable means of hair removal. Again it is only temporary although it may last 2-3 weeks longer temporary although it may last 2-3 weeks longer than shaving. However, it is costly and may be than shaving. However, it is costly and may be associated with pain and inflammation at the site. associated with pain and inflammation at the site.

Treatment of AnovulationTreatment of Anovulation Anovulation is the primary cause of infertility Anovulation is the primary cause of infertility

in about 20% of couples, and PCOS is in about 20% of couples, and PCOS is estimated to be the cause of 70% of estimated to be the cause of 70% of anovulatory fertility . There are many anovulatory fertility . There are many therapies for the induction of ovulation in therapies for the induction of ovulation in PCOS patients. The general paradigm is to PCOS patients. The general paradigm is to begin with the easiest to manage therapies, begin with the easiest to manage therapies, and if these do not result in ovulation or and if these do not result in ovulation or pregnancy in a reasonable period of time, to pregnancy in a reasonable period of time, to move on to more elaborate therapies. move on to more elaborate therapies.

Clomiphene CitrateClomiphene Citrate Clomiphene citrate is still the first line of Clomiphene citrate is still the first line of

therapy for ovulation induction in women therapy for ovulation induction in women with PCOS , although the argument has with PCOS , although the argument has been made that metformin is preferable . been made that metformin is preferable . The standard clomiphene regimen is 50 The standard clomiphene regimen is 50 mg /day for 5 days beginning on cycle day mg /day for 5 days beginning on cycle day 3-following spontaneous or progestin-3-following spontaneous or progestin-induced bleeding. If serum progesterone in induced bleeding. If serum progesterone in the mid luteal phase is less than 10 ng/mL, the mid luteal phase is less than 10 ng/mL, the dose can be increased by 50 mg a day the dose can be increased by 50 mg a day in subsequent cycles to a dose of 150 in subsequent cycles to a dose of 150 mg/day. mg/day.

MetforminMetformin Metformin in doses of 1500-1700 mg/day Metformin in doses of 1500-1700 mg/day

significantly increases rates of spontaneous significantly increases rates of spontaneous ovulation . ovulation .

GonadotropinsGonadotropins Options for women unresponsive to Options for women unresponsive to

standard or modified clomiphene citrate standard or modified clomiphene citrate stimulation therapies or to metformin alone stimulation therapies or to metformin alone include stimulation with gonadotropins or include stimulation with gonadotropins or surgically induced ovulation surgically induced ovulation

Surgical treatmentSurgical treatment

1.1. Ovarin wedge resection .is not done anymore Ovarin wedge resection .is not done anymore

2.2. Laparoscopic electro coagulation or laser Laparoscopic electro coagulation or laser electro coagulation.electro coagulation.

3.3. Ovarian drilling.Ovarian drilling.