Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

with infertility and desiring fertility

1st line – weight loss

Back
ACUTE
|
with infertility and desiring fertility
1st line – 

weight loss

The first-line and safest measure to restore ovulation is weight loss (in overweight or obese women). Weight loss alone (even as little as 5% to 7%) may restore ovulation in up to 80% of overweight or obese women (possibly by reducing hyperinsulinemia and thus hyperandrogenism).​[64][83]​​​​[84][85]​​​​​​ Weight loss is also beneficial from a cardiovascular standpoint, and may improve subsequent pregnancy outcomes.[87] Studies suggest dietary interventions, exercise, and/or behavioral coaching are effective for weight loss in polycystic ovary syndrome (PCOS), but no particular exercise or dietary composition (beyond caloric restriction) can be recommended over another.[64][81]​​[88]​​​​​

If weight loss is unsuccessful, pharmacologic ovulation induction therapy is recommended.

Guidelines recommend optimizing preconception health and lifestyle for all women with PCOS, but weight loss is not recommended as first-line fertility treatment for normal-weight women with PCOS.[53]​ In these women, letrozole or clomiphene should be first-line.

1st line – letrozole

Back
ACUTE
|
with infertility and desiring fertility
1st line – 

letrozole

The International PCOS Network and American College of Obstetricians and Gynecologists guidelines recommend letrozole as the first-line option for medical treatment of infertility in women with PCOS.[53][64]​​​​ Increasing data suggest that letrozole improves ovulation, pregnancy, and live birth rates compared with clomiphene.[89][91]​​​​​ However, the use of letrozole may be off-label in some countries, and some guidelines recommend clomiphene as the preferred option.[92]

The Pregnancy in Polycystic Ovary Syndrome II trial (PPCOS II, sample size 750) found that letrozole was superior to clomiphene in the live birth rate.[94] Meta-analyses of randomized controlled trials have found letrozole to be superior to clomiphene and similar to laparoscopic ovarian drilling for pregnancy and live birth.[90][91]​​​​​​ [ Cochrane Clinical Answers logo ] ​​Rates of miscarriage, ovarian hyperstimulation syndrome, and multiple pregnancies appear to be similar between letrozole and clomiphene.[90] [ Cochrane Clinical Answers logo ] ​​​

Primary options

letrozole: 2.5 mg orally once daily for 5 consecutive days initially, increase by 2.5 mg/day increments in subsequent cycles until ovulation is achieved, maximum 7.5 mg/day

1st line – clomiphene

Back
ACUTE
|
with infertility and desiring fertility
1st line – 

clomiphene

Clomiphene is a nonsteroidal antiestrogen that inhibits estrogen negative feedback on the hypothalamus/pituitary, which in turn leads to an increase in follicle-stimulating hormone secretion that may allow follicular maturation and ovulation.

A very commonly used fertility treatment and effective in achieving pregnancy.[106] Increasing data suggest that letrozole improves ovulation, pregnancy, and live birth rates compared with clomiphene.[89][91]​​ The International PCOS Network and American College of Obstetricians and Gynecologists guidelines recommend letrozole as the first-line option for pharmacologic treatment of infertility in women with PCOS.[53][64]​​​ However, use of letrozole may be off-label in some countries, and some guidelines recommend clomiphene as the preferred option.[92]

Up to 25% of patients will have clomiphene resistance due to ovarian unresponsiveness. There is a 5% to 10% risk of multiple pregnancy. In a clinical trial comparing clomiphene, metformin (and clomiphene plus metformin), multiple birth occurred in 6% of the clomiphene group and 0% of the metformin group (and in 3.1% in the clomiphene plus metformin group).[107]

A meta-analysis found that compared with early follicular phase administration of clomiphene, administration during the late luteal phase resulted in a higher total number of follicles, yet rates of ovulation and pregnancy were similar.[108]

Primary options

clomiphene: 50 mg orally once daily for 5 consecutive days initially, increase by 50 mg/day increments in subsequent cycles until ovulation achieved, maximum 150 mg/day

Consider – metformin

Back
ACUTE
|
with infertility and desiring fertility
Consider – 

metformin

Treatment recommended for SOME patients in selected patient group

If three treatment cycles of clomiphene have failed, it is reasonable to add metformin. Some studies, but not all, suggest that adding metformin to clomiphene may be efficacious if clomiphene alone is unsuccessful. It is also reasonable to start with clomiphene plus metformin rather than either agent alone as treatment of anovulatory infertility.[53]​ The 2023 International PCOS Network guideline suggests clomiphene plus metformin is preferred to clomiphene alone.[53]

A Cochrane review concluded that clomiphene plus metformin results in a 60% higher pregnancy rate compared with clomiphene alone, but data for live birth rates are inconclusive.[100] [ Cochrane Clinical Answers logo ] ​ Another meta-analysis comparing clomiphene plus metformin to clomiphene alone found the combination yielded a 28% higher clinical pregnancy rate but no differences in live birth rate.[109]​ However, in two randomized trials, clomiphene was similar in pregnancy or live birth rate to clomiphene plus metformin.[107][110]​ In one of these trials, metformin did not affect the dose of clomiphene needed to achieve ovulation.[111] In the other trial, subgroup analysis found metformin efficacious for pregnancy in older (age >28 years) women or those with increased central obesity.[112]

While adding metformin to clomiphene seems to improve ovulation rates, the impact on live birth rate has been questioned. Other meta-analyses found clomiphene plus metformin to increase pregnancy and live birth versus clomiphene alone in clomiphene-resistant women.[113][114]

To avoid gastrointestinal adverse effects, metformin should be taken with food and the dose titrated slowly over 4-6 weeks. Extended-release metformin has a slightly lower incidence of gastrointestinal adverse effects.

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

Consider – dexamethasone

Back
ACUTE
|
with infertility and desiring fertility
Consider – 

dexamethasone

Treatment recommended for SOME patients in selected patient group

If clomiphene fails to result in pregnancy, adding dexamethasone may be considered if the patient has evidence of adrenal androgen excess.

Suppression of adrenal androgen production with glucocorticoids may improve ovulatory function.

Adding dexamethasone to clomiphene improves the pregnancy rate compared with clomiphene alone.[106]

Primary options

dexamethasone: 0.25 to 0.5 mg orally once daily for 3-6 months

1st line – metformin

Back
ACUTE
|
with infertility and desiring fertility
1st line – 

metformin

Guidelines suggest that metformin alone is less effective than other ovulation induction agents, but it is associated with lower rates of multiple pregnancy, lower cost, and no monitoring requirements and may be considered as an alternative first-line option.[53] ​Metformin can restore ovulation/menses to the point where conception is possible. However, 6-9 months may be needed for the full effect.

Some data suggest that metformin may be less effective in women with a body mass index greater than 27-32 kg/m².[98][99][100] Patient characteristics that may predict metformin response have not been firmly identified. Some experts believe all women with PCOS may benefit, while others would give metformin only to women who are overweight/obese or who appear to have insulin resistance. One meta-analysis found that the rate of clinical pregnancy was slightly higher with metformin treatment compared with placebo (47.7% vs. 42.9%) for nonobese women with PCOS, but concluded more data is needed before metformin is recommended for nonobese women.[101]

Metformin appears to increase ovulation and pregnancy rates, but it has not conclusively been found to improve live birth rates.[100] [ Cochrane Clinical Answers logo ]

Meta-analyses suggest that continuing metformin throughout pregnancy may decrease rates of early pregnancy loss and premature birth, with no effect on gestational diabetes, preeclampsia, or fetal abnormalities.[102][103][104]​​ However, in a series of randomized trials, children born to women with polycystic ovary syndrome (PCOS) who were treated with metformin (from late first trimester to delivery) had increased body mass index compared with children born to women with PCOS in the placebo group.[105]

To avoid gastrointestinal adverse effects, metformin should be taken with food and the dose titrated slowly over 4-6 weeks. Extended-release metformin has a slightly lower incidence of gastrointestinal adverse effects. Metformin does not have adverse effects on the kidneys or liver in women with PCOS.[147]

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

2nd line – gonadotropins

Back
ACUTE
|
with infertility and desiring fertility
2nd line – 

gonadotropins

Gonadotropins (human menopausal gonadotropins [hMG]: luteinizing hormone plus follicle-stimulating hormone [FSH]) directly act on the ovary, stimulating follicular recruitment and maturation.

Gonadotropins are primarily recommended as a second-line option if other pharmacologic treatments are ineffective, but the 2023 International PCOS Network guideline recommends that they may be considered first-line as an alternative to clomiphene with or without metformin, acknowledging the increased cost, expertise, and monitoring requirements, and the potential for multiple pregnancy associated with gonadotropin treatment.[53]

In women with PCOS who have anovulatory infertility and clomiphene resistance, the International PCOS Network recommends that gonadotropins are preferable to clomiphene plus metformin, gonadotropins alone are preferred to gonadotropins plus clomiphene, and either gonadotropins or laparoscopic ovarian surgery can be offered.[53]

Treatment with gonadotropins is associated with a high risk of multiple pregnancies (twins in 20% to 30%, triplets in 1% to 2%) and ovarian hyperstimulation syndrome (OHSS), especially if many follicles reach intermediate size or if serum estradiol is too high. Mild OHSS (abdominal distention, nausea, vomiting, diarrhea) is common. Severe OHSS may cause extreme cystic ovarian enlargement (pain, hemorrhagic cysts, torsion), vascular hyperpermeability (ascites, hydrothorax, hypoproteinemia, electrolyte disturbance, hemoconcentration, oliguria, pulmonary edema), and, in the most severe cases, thrombosis (sometimes at unusual sites, e.g., subclavian or internal jugular vein) or thromboembolism.

Close follow-up and careful dosing are required to avoid OHSS.

In PCOS, lower doses of hMG are used because of the increased risk of OHSS compared with women without PCOS. FSH alone and hMG have similar rates of OHSS, pregnancy, and live birth.[115] Polycystic ovarian morphology is a risk factor for OHSS. Therefore, ultrasound evaluation of the ovaries may assist in selecting the initial dose of gonadotropins.

The step-up and step-down approaches with FSH were compared in clomiphene-resistant women with PCOS. The pregnancy rates did not differ, but the step-up approach had higher rates of ovulation and lower rates of OHSS.[116] Another trial found a sequential step-up and step-down protocol to have higher pregnancy and lower miscarriage rates then either step-up or step-down protocols.[117]

Primary options

follitropin alfa: consult specialist for guidance on dose

OR

follitropin beta: consult specialist for guidance on dose

Secondary options

menotropins: consult specialist for guidance on dose

Consider – metformin

Back
ACUTE
|
with infertility and desiring fertility
Consider – 

metformin

Treatment recommended for SOME patients in selected patient group

Gonadotropins are usually given as sole therapy; however, adding metformin might reduce the risk of ovarian hyperstimulation syndrome.[118][119]​ Preliminary evidence suggests that taking metformin during ovulation induction with gonadotropin, followed by timed intercourse or intrauterine insemination, might increase rates of pregnancy and live birth.[119][120][121]​​ [ Cochrane Clinical Answers logo ]

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

3rd line – in vitro fertilization

Back
ACUTE
|
with infertility and desiring fertility
3rd line – 

in vitro fertilization

In typical protocols, gonadotropins are given to promote multifollicular growth so that multiple mature oocytes can be aspirated. Despite more frequent cycle cancellation (failure to retrieve oocytes) and higher rates of miscarriage than in controls, women with polycystic ovary syndrome have more oocytes obtained per retrieval and similar pregnancy and live birth rates per cycle.[128][129]

There is a significant risk of ovarian hyperstimulation syndrome, which can be avoided by close monitoring, use of lower doses of gonadotropins, and early cycle cancellation.[115]

Consider – metformin

Back
ACUTE
|
with infertility and desiring fertility
Consider – 

metformin

Treatment recommended for SOME patients in selected patient group

While having no effect on live birth rates, giving metformin during assisted reproduction may increase clinical pregnancy rates and reduce ovarian hyperstimulation syndrome.[148] [ Cochrane Clinical Answers logo ] Meta-analyses found that while not impacting pregnancy or live birth rates, metformin administration during in vitro fertilization and intracytoplasmic sperm injection cycles may reduce the risk of ovarian hyperstimulation syndrome, and improve implantation rates.[130][131][132]

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

3rd line – laparoscopic ovarian drilling

Back
ACUTE
|
with infertility and desiring fertility
3rd line – 

laparoscopic ovarian drilling

Laparoscopic ovarian drilling (the use of electrocautery or laser to reduce the amount of functional ovarian tissue to reduce androgen production, also reduces inhibin production, allowing follicle-stimulating hormone to rise and stimulate ovarian aromatase) can restore ovulation and result in pregnancy rates of 25% to 65%.

No risk of hyperstimulation or multiple births, but risk of postoperative adhesion formation (much less than previous ovarian wedge resection techniques) and ovarian atrophy.[122]

One meta-analysis comparing laparoscopic ovarian drilling with medical induction of ovulation (including gonadotropins, clomiphene, letrozole, metformin, and others alone and in combination) in women with anovulatory polycystic ovary syndrome (PCOS) who had clomiphene resistance found a lower live birth rate with laparoscopic ovarian drilling; when the analysis was restricted to trials with a low risk of bias, the live birth rates were similar.[123] Furthermore, in women with anovulatory PCOS who had clomiphene resistance, laparoscopic ovarian drilling versus medical induction of ovulation was associated with similar rates of pregnancy and miscarriage but lower rates of multiple pregnancy and ovarian hyperstimulation syndrome.[123] [ Cochrane Clinical Answers logo ]

There is no conclusive evidence that laparoscopic ovarian drilling leads to diminished ovarian reserve or premature ovarian failure.[124]

Unilateral and bilateral ovarian drilling may have similar efficacy in clinical pregnancy and live birth rates.[125]

Lean (body mass index [BMI] <25 kg/m²) women may have better ovulatory and pregnancy responses to ovarian ablation than obese women.[126]

Ovarian drilling may be most effective in clomiphene-resistant women, with BMI <30 kg/m², and preoperative luteinizing hormone above 10 IU/L.[127]

ONGOING

not desiring current fertility

1st line – oral contraceptive pill

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
1st line – 

oral contraceptive pill

Weight loss should be encouraged, but is less efficacious for androgenic symptoms than for therapy of infertility or infrequent/reduced menstrual bleeding.

In most women with hyperandrogenic symptoms, an oral contraceptive pill (OCP: cyclic estrogen plus a progestin) is an appropriate choice of initial treatment. All pharmacologic therapies for hirsutism should be trialed at least 6 months before making changes in dose, switching to a new medication, or adding medication.[12][78]

The Endocrine Society hirsutism clinical practice guidelines and the International PCOS Network guidelines do not recommend one particular OCP over another.​[53]​​[78]​ OCPs are more effective for acne than for hirsutism.

OCP therapy modestly inhibits gonadotropin secretion, and thus gonadotropin-sensitive ovarian androgen production, and increases hepatic production of sex hormone-binding globulin (SHBG), which further decreases free testosterone. If free testosterone and SHBG are not normalized after 3 months, the possibility of an androgen-secreting neoplasm should be considered.

Levonorgestrel is the most androgenic progestin and OCPs that contain a progestin with androgenic activity (e.g., levonorgestrel, norethindrone) have often been avoided in practice due to concerns they would be less effective for symptoms like hirsutism. This was not observed in meta-analysis.[133] However, levonorgestrel can have an adverse effect on metabolic biomarkers and therefore it tends to be avoided in women with PCOS.[78] Newer, less-androgenic progestins include desogestrel or norgestimate.

Drospirenone is a spironolactone analog with antiandrogenic and antimineralocorticoid properties. Pills with these newer, lower-androgenicity progestins may, however, confer a higher risk of venous thromboembolism than older pills,​ although one large prospective study found no such risk.[134][135][136][137] Given this possible risk of venous thromboembolism with newer pills, some practitioners still prefer to use levonorgestrel- or norethindrone-containing pills.

OCPs should not be used before epiphyseal closure. Caution is advised if cardiovascular risk factors are present.[149] Contraceptive pills should be avoided or used with caution in women with risk factors (e.g., smoking [especially if age is ≥35 years], history of thromboembolism, or migraine with aura). Other reasons for caution include poorly controlled hypertension, diabetes of long duration (>20 years), and diabetes with vascular complications.[138]​​

Various OCPs are available; consult your local drug formulary for more information.

Consider – metformin

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
Consider – 

metformin

Treatment recommended for SOME patients in selected patient group

The choice of agents to use is individualized, taking into account the clinical picture and preferences regarding adverse effects.

For the specific goal of treating hyperandrogenism, metformin is best suited as add-on therapy to oral contraceptive pills (OCPs), antiandrogens, or OCPs plus antiandrogens. The Endocrine Society advises against using insulin-lowering drugs for the sole indication of treating hirsutism.[78] Metformin is associated with decreased testosterone and androstenedione levels and increased sex hormone-binding globulin levels, with limited evidence of improvement in hirsutism.[133][139][140][141]​​​ However, adding metformin might improve results compared with monotherapy or dual therapy.[133][141]​​

Limited evidence suggests that metformin may promote weight loss, particularly at higher doses (>1500 mg/day) and with longer duration of therapy (>8 weeks).[144]​ A meta-analysis of 51 studies concluded that metformin (alone or as adjuvant therapy) may improve acne scores.[142]

The 2023 International PCOS guideline suggests that the combination of OCPs and metformin may be most beneficial in high risk metabolic groups, including women with BMI >30 kg/m², risk factors for diabetes, impaired glucose tolerance, or high-risk ethnic groups.[53]

To avoid gastrointestinal adverse effects, metformin should be taken with food and the dose titrated slowly over 4-6 weeks. Extended-release metformin has a slightly lower incidence of gastrointestinal adverse effects.

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

Consider – mechanical hair removal or topical therapy

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
Consider – 

mechanical hair removal or topical therapy

Treatment recommended for SOME patients in selected patient group

Medical therapy for hirsutism is more effective in impeding or slowing further growth than in regressing hair growth. (Terminal hairs generally do not revert to vellus.)

Adjunctive mechanical removal is recommended (does not worsen hirsutism). Endocrine therapy leads to thinner (less visible) hair shafts, and longer telogen (resting) phase (fewer hairs at any time). To destroy terminal hair follicles, electrolysis (or laser, which works best with light skin and dark hair) is useful after ≥6 months of hormonal therapy has halted the appearance of new terminal hairs.

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks.[145]​ It should be discontinued if no results are noted by 4-6 months.

For androgenic alopecia, topical minoxidil treatment may be effective but must be used for several months.[146]

With both topical eflornithine and minoxidil, benefit subsides if the agent is discontinued.

Primary options

eflornithine topical: (13.9%) apply sparingly to the affected area(s) twice daily

OR

minoxidil topical: (2% to 5%) apply 1 mL to scalp twice daily

2nd line – antiandrogen

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
2nd line – 

antiandrogen

Weight loss should be encouraged, but is less efficacious for androgenic symptoms than for therapy of infertility or infrequent/reduced menstrual bleeding.

The Endocrine Society advises against antiandrogen monotherapy as initial therapy for hirsutism because of its teratogenic potential (unless women are on adequate contraception).[78] For women who are not sexually active, have undergone permanent sterilization, or are on long-acting reversible contraception, initial therapy with oral contraceptive pill or antiandrogens as monotherapy are both options.[78] If monotherapy is to be used, the decision is tailored to the woman's needs, with a particular focus on adverse effects.

Women with severe hirsutism or contraindications to hormonal contraception may need to be considered for treatment with antiandrogens.[31][78]​​​​

Antiandrogens are androgen receptor blockers (e.g., spironolactone, cyproterone) or 5-alpha-reductase inhibitors (e.g., finasteride). Cyproterone is not available in the US.

Antiandrogens (especially finasteride) should be avoided in pregnancy due to potential for ambiguous genitalia in male fetus. Antiandrogens should be used for at least 6 months before judging efficacy.[78] The maximal effect on hirsutism may take 9-12 months (compared with the effect on acne, which usually responds within 2 months). Acne is more responsive to therapy while alopecia is less responsive.

Contraceptive measures are advisable given theoretical teratogenicity.

Primary options

spironolactone: 50-100 mg orally twice daily

Secondary options

finasteride: 5 mg orally once daily

Consider – metformin

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
Consider – 

metformin

Treatment recommended for SOME patients in selected patient group

The choice of agents to use is individualized, taking into account the clinical picture and preferences regarding adverse effects.

For the specific goal of treating hyperandrogenism, metformin is best suited as add-on therapy to oral contraceptive pills (OCPs), antiandrogens, or OCPs plus antiandrogens. The Endocrine Society advises against using insulin-lowering drugs for the sole indication of treating hirsutism.[78] Metformin is associated with decreased testosterone and androstenedione levels and increased sex hormone-binding globulin levels, with limited evidence of improvement in hirsutism.[133][139][140][141] ​However, adding metformin might improve results compared with monotherapy or dual therapy.[133][141]​​

Limited evidence suggests that metformin may promote weight loss, particularly at higher doses (>1500 mg/day) and with longer duration of therapy (>8 weeks).[144]​ A meta-analysis of 51 studies concluded that metformin (alone or as adjuvant therapy) may improve acne scores.[142]

To avoid gastrointestinal adverse effects, metformin should be taken with food and the dose titrated slowly over 4-6 weeks. Extended-release metformin has a slightly lower incidence of gastrointestinal adverse effects.

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

Consider – mechanical hair removal or topical therapy

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
Consider – 

mechanical hair removal or topical therapy

Treatment recommended for SOME patients in selected patient group

Medical therapy for hirsutism is more effective in impeding or slowing further growth than in regressing hair growth. (Terminal hairs generally do not revert to vellus.)

Adjunctive mechanical removal is recommended (does not worsen hirsutism). Endocrine therapy leads to thinner (less visible) hair shafts, and longer telogen (resting) phase (fewer hairs at any time). To destroy terminal hair follicles, electrolysis (or laser, which works best with light skin and dark hair) is useful after ≥6 months of hormonal therapy has halted the appearance of new terminal hairs.

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks.[145]​ It should be discontinued if no results are noted by 4-6 months.

For androgenetic alopecia, topical minoxidil treatment may be effective but must be used for several months.[146]

With both topical eflornithine and minoxidil, benefit subsides if the agent is discontinued.

Primary options

eflornithine topical: (13.9%) apply sparingly to the affected area(s) twice daily

OR

minoxidil topical: (2% to 5%) apply 1 mL to scalp twice daily

2nd line – antiandrogen plus oral contraceptive pill

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
2nd line – 

antiandrogen plus oral contraceptive pill

The choice of agents to use is individualized, taking into account the clinical picture and preferences regarding adverse effects.

In many cases, a combination of antiandrogen and oral contraceptive may be needed, particularly for hirsutism or severe acne. The combination has the added benefit of preventing pregnancy, while increasing efficacy by targeting two different processes: androgen production and androgen action.

The Endocrine Society recommends monotherapy first line for hirsutism, and if symptoms remain after 6 months to add in an antiandrogen.[78] All pharmacologic therapies for hirsutism should be trialed at least 6 months before making changes in dose, switching to a new medication, or adding medication.[12][78]

Antiandrogens are androgen receptor blockers (e.g., spironolactone, cyproterone) or 5-alpha-reductase inhibitors (e.g., finasteride). Cyproterone is not available in the US.

Contraceptive measures are advisable with antiandrogens given theoretical teratogenicity. Antiandrogens (especially finasteride) should be avoided in pregnancy due to potential for ambiguous genitalia in male fetus.

Various OCPs are available; consult your local drug formulary for more information.

Primary options

spironolactone: 50-100 mg orally twice daily

Secondary options

finasteride: 5 mg orally once daily

Consider – metformin

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
Consider – 

metformin

Treatment recommended for SOME patients in selected patient group

The choice of agents to use is individualized, taking into account the clinical picture and preferences regarding adverse effects.

For the specific goal of treating hyperandrogenism, metformin is best suited as add-on therapy to oral contraceptive pills (OCPs), antiandrogens, or OCPs plus antiandrogens. The Endocrine Society advises against using insulin-lowering drugs for the sole indication of treating hirsutism.[78] Metformin is associated with decreased testosterone and androstenedione levels and increased sex hormone-binding globulin levels, with limited evidence of improvement in hirsutism.[133][139][140][141] However, adding metformin might improve results compared with monotherapy or dual therapy.[133][141]​​

Limited evidence suggests that metformin may promote weight loss, particularly at higher doses (>1500 mg/day) and with longer duration of therapy (>8 weeks).[144]​ A meta-analysis of 51 studies concluded that metformin (alone or as adjuvant therapy) may improve acne scores.[142]

To avoid gastrointestinal adverse effects, metformin should be taken with food and the dose titrated slowly over 4-6 weeks. Extended-release metformin has a slightly lower incidence of gastrointestinal adverse effects.

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

Consider – mechanical hair removal or topical therapy

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
Consider – 

mechanical hair removal or topical therapy

Treatment recommended for SOME patients in selected patient group

Medical therapy for hirsutism is more effective in impeding or slowing further growth than in regressing hair growth. (Terminal hairs generally do not revert to vellus.)

Adjunctive mechanical removal is recommended (does not worsen hirsutism). Endocrine therapy leads to thinner (less visible) hair shafts, and longer telogen (resting) phase (fewer hairs at any time). To destroy terminal hair follicles, electrolysis (or laser, which works best with light skin and dark hair) is useful after ≥6 months of hormonal therapy has halted the appearance of new terminal hairs.

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks.[145]​ It should be discontinued if no results are noted by 4-6 months.

For androgenetic alopecia, topical minoxidil treatment may be effective but must be used for several months.[146]

With both topical eflornithine and minoxidil, benefit subsides if the agent is discontinued.

Primary options

eflornithine topical: (13.9%) apply sparingly to the affected area(s) twice daily

OR

minoxidil topical: (2% to 5%) apply 1 mL to scalp twice daily

3rd line – long-acting GnRH analog plus oral contraceptive pill

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
3rd line – 

long-acting GnRH analog plus oral contraceptive pill

Weight loss should be encouraged, but is less efficacious for androgenic symptoms than for therapy of infertility or infrequent/reduced menstrual bleeding.

Long-acting gonadotropin-releasing hormone (GnRH) analogs (e.g., leuprolide) yield profound suppression of gonadotropins and suppress ovarian steroid synthesis.

Only to be used in severe or refractory ovarian hyperandrogenism.[78]​ GnRH agonists are best combined with estrogen (oral contraceptive pills) to increase sex hormone-binding globulin and protect bones from resultant hypoestrogenemia (women on GnRH without estrogen replacement may lose 4% to 8% trabecular bone after 6 months) and avoid severe vasomotor symptoms.

With the estrogen replacement, a progestin must also be given to protect the endometrium.[78]

Various OCPs are available; consult your local drug formulary for more information.

Primary options

leuprolide: 3.75 mg intramuscularly once monthly; 11.25 mg intramuscularly every 3 months

Consider – mechanical hair removal or topical therapy

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features alone
Consider – 

mechanical hair removal or topical therapy

Treatment recommended for SOME patients in selected patient group

Medical therapy for hirsutism is more effective in impeding or slowing further growth than in regressing hair growth. (Terminal hairs generally do not revert to vellus.)

Adjunctive mechanical removal is recommended (does not worsen hirsutism). Endocrine therapy leads to thinner (less visible) hair shafts, and longer telogen (resting) phase (fewer hairs at any time). To destroy terminal hair follicles, electrolysis (or laser, which works best with light skin and dark hair) is useful after ≥6 months of hormonal therapy has halted the appearance of new terminal hairs.

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks.[145]​ It should be discontinued if no results are noted by 4-6 months.

For androgenetic alopecia, topical minoxidil treatment may be effective but must be used for several months.[146]

With both topical eflornithine and minoxidil, benefit subsides if the agent is discontinued.

Primary options

eflornithine topical: (13.9%) apply sparingly to the affected area(s) twice daily

OR

minoxidil topical: (2% to 5%) apply 1 mL to scalp twice daily

1st line – weight loss

Back
ONGOING
|
not desiring current fertility
|
with infrequent/reduced menstrual bleeding alone
1st line – 

weight loss

Anovulatory women with polycystic ovary syndrome (PCOS) have chronic estrogenization without progesterone exposure, leading to risk of abnormal uterine bleeding, endometrial hyperplasia, and cancer. Therefore, treatments that induce ovulation or provide progesterone exposure should be given.

Weight loss is the preferred treatment for overweight or obese women. The oral contraceptive pill or metformin is used if ineffective, or if weight is normal.

Weight loss alone (even as little as 5% to 7%) may restore ovulation in up to 80% of overweight or obese women (possibly by reducing hyperinsulinemia and thus hyperandrogenism).[64][83]​​​[84][85]​​​ Studies suggest dietary interventions, exercise, and/or behavioral coaching are effective for weight loss in PCOS, but no particular exercise or dietary composition (beyond caloric restriction) can be recommended over another.[64][81][88]​​

2nd line – oral contraceptive pill

Back
ONGOING
|
not desiring current fertility
|
with infrequent/reduced menstrual bleeding alone
2nd line – 

oral contraceptive pill

The progestin withdrawal results in menses and negates risk of endometrial hyperplasia.

Among the older oral contraceptive pills (OCPs), ethynodiol/ethinyl estradiol is considered low androgenic and may be useful if a larger dose of estrogen is needed. This higher-estrogen-dose pill may be able to induce menses in women with persistent amenorrhea. Persistent amenorrhea may indicate endometrial atrophy resulting from hyperandrogenism (thin endometrial width on ultrasound). The risk-benefit ratio must be carefully considered when using higher-dose pills.

OCPs should not be used before epiphyseal closure. Avoid or use with caution in women with risk factors (e.g., smoking [especially if age is ≥35 years], history of thromboembolism, or migraine with aura). Other reasons for caution include poorly controlled hypertension, diabetes of long duration (>20 years), and diabetes with vascular complications.[138]

Pills with newer, lower-androgenicity progestins (e.g., desogestrel, norgestimate) may confer a higher risk of venous thromboembolism than older pills,​ although one large prospective study found no such risk.[134][135][136][137] Given this possible risk of venous thromboembolism with newer pills, some practitioners still prefer to use levonorgestrel- or norethindrone-containing pills.

The International PCOS Network guidelines do not recommend a particular OCP over another.[53]

Various OCPs are available; consult your local drug formulary for more information.

2nd line – metformin

Back
ONGOING
|
not desiring current fertility
|
with infrequent/reduced menstrual bleeding alone
2nd line – 

metformin

May be used to improve menstrual irregularity.

To avoid gastrointestinal adverse effects, metformin should be taken with food and the dose titrated slowly over 4-6 weeks. Extended-release metformin has a slightly lower incidence of gastrointestinal adverse effects.

Limited evidence suggests that metformin may promote weight loss, particularly at higher doses (>1500 mg/day) and with longer duration of therapy (>8 weeks).[144]

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

3rd line – cyclic progestin

Back
ONGOING
|
not desiring current fertility
|
with infrequent/reduced menstrual bleeding alone
3rd line – 

cyclic progestin

Should be given if the oral contraceptive pill (OCP) is not tolerated or desired by the patient, or if there are contraindications to an OCP.[31]​​ A cyclic progestin is also used in refractory cases.

Primary options

progesterone micronized: 200-400 mg orally once daily for 10 days each month

OR

medroxyprogesterone: 5-10 mg orally once daily for 10 days each month

Secondary options

norethindrone: 2.5 to 10 mg orally once daily for 10 days each month

1st line – weight loss

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features plus infrequent/reduced menstrual bleeding
1st line – 

weight loss

Women with hyperandrogenic features plus infrequent/reduced menstrual bleeding are treated with a combined approach. Preferred treatment is weight loss (if overweight) plus the oral contraceptive pill.

Weight loss alone (even as little as 5% to 7%) may restore ovulation in up to 80% of overweight or obese women (possibly by reducing hyperinsulinemia and thus hyperandrogenism).[64][83]​​​​[84][85]​​​​ Studies suggest dietary interventions, exercise, and/or behavioral coaching are effective for weight loss in polycystic ovary syndrome, but no particular exercise or dietary composition (beyond caloric restriction) can be recommended over another.[64][81]​​[88]​​​​

Plus – oral contraceptive pill

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features plus infrequent/reduced menstrual bleeding
Plus – 

oral contraceptive pill

Treatment recommended for ALL patients in selected patient group

Oral contraceptive pill (OCP: cyclic estrogen plus a progestin) therapy modestly inhibits gonadotropin secretion, and thus gonadotropin-sensitive ovarian androgen production, and increases hepatic production of sex hormone-binding globulin (SHBG), which further decreases free testosterone. If free testosterone and SHBG are not normalized after 3 months, the possibility of an androgen-secreting neoplasm should be considered.

OCPs with progestins with androgenic activity (e.g., levonorgestrel, norethindrone) should be avoided. Newer, less-androgenic progestins include desogestrel and norgestimate.

Drospirenone is a spironolactone analog with antiandrogenic and antimineralocorticoid properties. Pills with these newer, lower-androgenicity progestins may, however, confer a higher risk of venous thromboembolism than older pills,​ although one large prospective study found no such risk.[134][135][136][137]​ Given this possible risk of venous thromboembolism with newer pills, some practitioners still prefer to use levonorgestrel- or norethindrone-containing pills. The International PCOS Network guidelines do not recommend a particular OCP over another.[53]

OCPs should not be used before epiphyseal closure. Caution is advised if cardiovascular risk factors are present.[149] OCPs should be avoided or used with caution in women with risk factors (e.g., smoking [especially if age is ≥35 years], history of thromboembolism, or migraine with aura). Other reasons for caution include poorly controlled hypertension, diabetes of long duration (>20 years), and diabetes with vascular complications.[138]

Various OCPs are available; consult your local drug formulary for more information.

Consider – metformin

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features plus infrequent/reduced menstrual bleeding
Consider – 

metformin

Treatment recommended for SOME patients in selected patient group

The choice of agents to use is individualized, taking into account the clinical picture and preferences regarding adverse effects.

For the specific goal of treating hyperandrogenism, metformin is best suited as add-on therapy to oral contraceptive pills (OCPs), antiandrogens, or OCPs plus antiandrogens. The Endocrine Society advises against using insulin-lowering drugs for the sole indication of treating hirsutism.[78]​ Metformin is associated with decreased testosterone and androstenedione levels and increased sex hormone-binding globulin levels, with limited evidence of improvement in hirsutism.[133][139][140][141] However, adding metformin might improve results compared with monotherapy or dual therapy.[133][141]​​

Limited evidence suggests that metformin may promote weight loss, particularly at higher doses (>1500 mg/day) and with longer duration of therapy (>8 weeks).[144]​ A meta-analysis of 51 studies concluded that metformin (alone or as adjuvant therapy) may improve acne scores.[142]

To avoid gastrointestinal adverse effects, metformin should be taken with food and the dose titrated slowly over 4-6 weeks. Extended-release metformin has a slightly lower incidence of gastrointestinal adverse effects.

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

Consider – mechanical hair removal or topical therapy

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features plus infrequent/reduced menstrual bleeding
Consider – 

mechanical hair removal or topical therapy

Treatment recommended for SOME patients in selected patient group

Medical therapy for hirsutism is more effective in impeding or slowing further growth than in regressing hair growth. (Terminal hairs generally do not revert to vellus.)

Adjunctive mechanical removal is recommended (does not worsen hirsutism). Endocrine therapy leads to thinner (less visible) hair shafts, and longer telogen (resting) phase (fewer hairs at any time). To destroy terminal hair follicles, electrolysis (or laser, which works best with light skin and dark hair) is useful after ≥6 months of hormonal therapy has halted the appearance of new terminal hairs.

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks, and facial hair returns if eflornithine is discontinued.[145]​ It should be discontinued if no results are noted by 4-6 months.

For androgenetic alopecia, topical minoxidil treatment may be effective but must be used for several months.[146]

With both topical eflornithine and minoxidil, benefit subsides if the agent is discontinued.

Primary options

eflornithine topical: (13.9%) apply sparingly to the affected area(s) twice daily

OR

minoxidil topical: (2% to 5%) apply 1 mL to scalp twice daily

2nd line – antiandrogen plus oral contraceptive pill

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features plus infrequent/reduced menstrual bleeding
2nd line – 

antiandrogen plus oral contraceptive pill

Weight loss should be encouraged in overweight women.

The choice of agents to use is individualized, taking into account the clinical picture and preferences regarding adverse effects.

Oral contraceptive pills are more effective for acne than for hirsutism. A combination with antiandrogens is usually necessary for hirsutism or severe acne. The combination has the added benefit of preventing pregnancy, while increasing efficacy by targeting two different processes: androgen production and androgen action.

Antiandrogens are androgen receptor blockers (e.g., spironolactone, cyproterone) or 5-alpha-reductase inhibitors (e.g., finasteride). Cyproterone is not available in the US.

Contraceptive measures are advisable with antiandrogens given theoretical teratogenicity. Finasteride is particularly dangerous to a male fetus.

Various oral contraceptive pills are available; consult your local drug formulary for more information.

Primary options

spironolactone: 50-100 mg orally twice daily

Secondary options

finasteride: 5 mg orally once daily

Consider – metformin

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features plus infrequent/reduced menstrual bleeding
Consider – 

metformin

Treatment recommended for SOME patients in selected patient group

The choice of agents to use is individualized, taking into account the clinical picture and preferences regarding adverse effects.

For the specific goal of treating hyperandrogenism, metformin is best suited as add-on therapy to oral contraceptive pills (OCPs), antiandrogens, or OCPs plus antiandrogens. The Endocrine Society advises against using insulin-lowering drugs for the sole indication of treating hirsutism.[78]​ Metformin is associated with decreased testosterone and androstenedione levels and increased sex hormone-binding globulin levels, with limited evidence of improvement in hirsutism.[133][139][140][141]​ However, adding metformin might improve results compared with monotherapy or dual therapy.[133][141]​​

Limited evidence suggests that metformin may promote weight loss, particularly at higher doses (>1500 mg/day) and with longer duration of therapy (>8 weeks).[144]​ A meta-analysis of 51 studies concluded that metformin (alone or as adjuvant therapy) may improve acne scores.[142]

To avoid gastrointestinal adverse effects, metformin should be taken with food and the dose titrated slowly over 4-6 weeks. Extended-release metformin has a slightly lower incidence of gastrointestinal adverse effects.

Primary options

metformin: 500 mg orally (immediate-release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily

Consider – mechanical hair removal or topical therapy

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features plus infrequent/reduced menstrual bleeding
Consider – 

mechanical hair removal or topical therapy

Treatment recommended for SOME patients in selected patient group

Medical therapy for hirsutism is more effective in impeding or slowing further growth than in regressing hair growth. (Terminal hairs generally do not revert to vellus.)

Adjunctive mechanical removal is recommended (does not worsen hirsutism). Endocrine therapy leads to thinner (less visible) hair shafts, and longer telogen (resting) phase (fewer hairs at any time). To destroy terminal hair follicles, electrolysis (or laser, which works best with light skin and dark hair) is useful after ≥6 months of hormonal therapy has halted the appearance of new terminal hairs.

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks, and facial hair returns if eflornithine is discontinued.[145]​ It should be discontinued if no results are noted by 4-6 months.

For androgenetic alopecia, topical minoxidil treatment may be effective but must be used for several months.[146]

With both topical eflornithine and minoxidil, benefit subsides if the agent is discontinued.

Primary options

eflornithine topical: (13.9%) apply sparingly to the affected area(s) twice daily

OR

minoxidil topical: (2% to 5%) apply 1 mL to scalp twice daily

3rd line – long-acting GnRH analog plus oral contraceptive pill

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features plus infrequent/reduced menstrual bleeding
3rd line – 

long-acting GnRH analog plus oral contraceptive pill

Weight loss should be encouraged in overweight women.

Long-acting gonadotropin-releasing hormone (GnRH) analogs (e.g., leuprolide) yield profound suppression of gonadotropins and suppress ovarian steroid synthesis.

Only to be used in severe or refractory ovarian hyperandrogenism.[78]​ GnRH agonists are best combined with estrogen (oral contraceptive pills) to increase sex hormone-binding globulin and protect bones from resultant hypoestrogenemia (women on GnRH without estrogen replacement may lose 4% to 8% trabecular bone after 6 months) and avoid severe vasomotor symptoms.

With the estrogen replacement, a progestin must also be given to protect the endometrium.[78]

Various oral contraceptive pills are available; consult your local drug formulary for more information.

Primary options

leuprolide: 3.75 mg intramuscularly once monthly; 11.25 mg intramuscularly every 3 months

Consider – mechanical hair removal or topical therapy

Back
ONGOING
|
not desiring current fertility
|
with hyperandrogenic features plus infrequent/reduced menstrual bleeding
Consider – 

mechanical hair removal or topical therapy

Treatment recommended for SOME patients in selected patient group

Medical therapy for hirsutism is more effective in impeding or slowing further growth than in regressing hair growth. (Terminal hairs generally do not revert to vellus.)

Adjunctive mechanical removal is recommended (does not worsen hirsutism). Endocrine therapy leads to thinner (less visible) hair shafts, and longer telogen (resting) phase (fewer hairs at any time). To destroy terminal hair follicles, electrolysis (or laser, which works best with light skin and dark hair) is useful after ≥6 months of hormonal therapy has halted the appearance of new terminal hairs.

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks, and facial hair returns if eflornithine is discontinued.[145]​ It should be discontinued if no results are noted by 4-6 months.

For androgenetic alopecia, topical minoxidil treatment may be effective but must be used for several months.[146]

With both topical eflornithine and minoxidil, benefit subsides if the agent is discontinued.

Primary options

eflornithine topical: (13.9%) apply sparingly to the affected area(s) twice daily

OR

minoxidil topical: (2% to 5%) apply 1 mL to scalp twice daily

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