Polycystic ovary syndrome

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

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

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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 hyperinsulinaemia and thus hyper-androgenism).[64][80][81][82] Weight loss is also beneficial from a cardiovascular standpoint, and may improve subsequent pregnancy outcomes.[84] Studies suggest dietary interventions, exercise, and/or behavioural 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][78][85]

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

Guidelines recommend optimising pre-conception 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 clomifene should be first-line.

1st line – letrozole

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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 clomifene.[86][88] However, the use of letrozole may be off-label in some countries, and some guidelines recommend clomifene as the preferred option.[89]

The Pregnancy in Polycystic Ovary Syndrome II trial (PPCOS II, sample size 750) found that letrozole was superior to clomifene in the live birth rate.[91] Meta-analyses of randomised controlled trials have found letrozole to be superior to clomifene and similar to laparoscopic ovarian drilling for pregnancy and live birth.[87][88] [ ] Rates of miscarriage, ovarian hyperstimulation syndrome, and multiple pregnancies appear to be similar between letrozole and clomifene.[87] [ ]

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 – clomifene

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1st line –

clomifene

Clomifene is a non-steroidal anti-oestrogen that inhibits oestrogen 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.[103] Increasing data suggest that letrozole improves ovulation, pregnancy, and live birth rates compared with clomifene.[86][88] The International PCOS Network and American College of Obstetricians and Gynecologists guidelines recommend letrozole as the first-line option for pharmacological treatment of infertility in women with PCOS.[53][64] However, use of letrozole may be off-label in some countries, and some guidelines recommend clomifene as the preferred option.[89]

Up to 25% of patients will have clomifene resistance due to ovarian unresponsiveness. There is a 5% to 10% risk of multiple pregnancy. In a clinical trial comparing clomifene, metformin (and clomifene plus metformin), multiple birth occurred in 6% of the clomifene group and 0% of the metformin group (and in 3.1% in the clomifene plus metformin group).[104]

A meta-analysis found that compared with early follicular phase administration of clomifene, administration during the late luteal phase resulted in a higher total number of follicles, yet rates of ovulation and pregnancy were similar.[105]

Primary options

clomifene: 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

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Consider –

metformin

Additional treatment recommended for SOME patients in selected patient group

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

A Cochrane review concluded that clomifene plus metformin results in a 60% higher pregnancy rate compared with clomifene alone, but data for live birth rates are inconclusive.[97] [ ] Another meta-analysis comparing clomifene plus metformin to clomifene alone found the combination yielded a 28% higher clinical pregnancy rate but no differences in live birth rate.[106] However, in two randomised trials, clomifene was similar in pregnancy or live birth rate to clomifene plus metformin.[104][107] In one of these trials, metformin did not affect the dose of clomifene needed to achieve ovulation.[108] In the other trial, sub-group analysis found metformin efficacious for pregnancy in older (age >28 years) women or those with increased central obesity.[109]

While adding metformin to clomifene seems to improve ovulation rates, the impact on live birth rate has been questioned. Other meta-analyses found clomifene plus metformin to increase pregnancy and live birth versus clomifene alone in clomifene-resistant women.[110][111]

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

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Consider –

dexamethasone

Additional treatment recommended for SOME patients in selected patient group

If clomifene 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 clomifene improves the pregnancy rate compared with clomifene alone.[103]

Primary options

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

1st line – metformin

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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.[95][96][97] Patient characteristics that may predict metformin response have not been firmly identified. Some experts believe all women with polycystic ovary syndrome (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 non-obese women with PCOS, but concluded more data is needed before metformin is recommended for non-obese women.[98]

Metformin appears to increase ovulation and pregnancy rates, but it has not conclusively been found to improve live birth rates.[97] [ ]

Meta-analyses suggest that continuing metformin throughout pregnancy may decrease rates of early pregnancy loss and premature birth, with no effect on gestational diabetes, pre-eclampsia, or fetal abnormalities.[99][100][101] However, in a series of randomised trials, children born to women with 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.[102]

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 – gonadotrophins

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2nd line –

gonadotrophins

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

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

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

Treatment with gonadotrophins 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 distension, nausea, vomiting, diarrhoea) is common. Severe OHSS may cause extreme cystic ovarian enlargement (pain, haemorrhagic cysts, torsion), vascular hyperpermeability (ascites, hydrothorax, hypoproteinaemia, electrolyte disturbance, haemoconcentration, oliguria, pulmonary oedema), 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.[112] Polycystic ovarian morphology is a risk factor for OHSS. Therefore, ultrasound evaluation of the ovaries may assist in selecting the initial dose of gonadotrophins.

The step-up and step-down approaches with FSH were compared in clomifene-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.[113] 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.[114]

Primary options

follitropin alfa: consult specialist for guidance on dose

follitropin beta: consult specialist for guidance on dose

Secondary options

menotrophin: consult specialist for guidance on dose

Consider – metformin

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Consider –

metformin

Additional treatment recommended for SOME patients in selected patient group

Gonadotrophins are usually given as sole therapy; however, adding metformin might reduce the risk of ovarian hyperstimulation syndrome.[115][116] Preliminary evidence suggests that taking metformin during ovulation induction with gonadotrophin, followed by timed intercourse or intrauterine insemination, might increase rates of pregnancy and live birth.[116][117][118] [ ]

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 fertilisation

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3rd line –

in vitro fertilisation

In typical protocols, gonadotrophins are given to promote multi-follicular 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.[125][126]

There is a significant risk of ovarian hyperstimulation syndrome, which can be avoided by close monitoring, use of lower doses of gonadotrophins, and early cycle cancellation.[112]

Consider – metformin

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Consider –

metformin

Additional 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.[146] [ ] Meta-analyses found that while not impacting pregnancy or live birth rates, metformin administration during in vitro fertilisation and intracytoplasmic sperm injection cycles may reduce the risk of ovarian hyper-stimulation syndrome, and improve implantation rates.[127][128][129]

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

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3rd line –

laparoscopic ovarian drilling

Laparoscopic ovarian drilling (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.[119]

One meta-analysis comparing laparoscopic ovarian drilling with medical induction of ovulation (including gonadotrophins, clomifene, letrozole, metformin, and others alone and in combination) in women with anovulatory polycystic ovary syndrome (PCOS) who had clomifene 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.[120] Furthermore, in women with anovulatory PCOS who had clomifene 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.[120] [ ]

There is no conclusive evidence that laparoscopic ovarian drilling leads to diminished ovarian reserve or premature ovarian failure.[121]

Unilateral and bilateral ovarian drilling may have similar efficacy in clinical pregnancy and live birth rates.[122]

Lean (body mass index [BMI] <25 kg/m²) women may have better ovulatory and pregnancy responses to ovarian ablation than obese women.[123]

Ovarian drilling may be most effective in clomifene-resistant women, with BMI <30 kg/m², and preoperative luteinising hormone above 10 IU/L.[124]

ONGOING

not desiring current fertility

with hyper-androgenic features alone

1st line – oral contraceptive pill

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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 oestrogen plus a progestin) is an appropriate choice of initial treatment. All pharmacological therapies for hirsutism should be trialed at least 6 months before making changes in dose, switching to a new medication, or adding medication.[12][130]

The Endocrine Society hirsutism clinical practice guidelines and the International PCOS Network guidelines do not recommend one particular OCP over another.[53][130] OCPs are more effective for acne than for hirsutism.

OCP therapy modestly inhibits gonadotrophin secretion, and thus gonadotrophin-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 normalised 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, norethisterone) 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.[131] However, levonorgestrel can have an adverse effect on metabolic biomarkers and therefore it tends to be avoided in women with PCOS.[130] Newer, less-androgenic progestins include desogestrel or norgestimate.

Drospirenone is a spironolactone analogue with anti-androgenic and anti-mineralocorticoid 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.[132][133][134][147] Given this possible risk of venous thromboembolism with newer pills, some practitioners still prefer to use levonorgestrel- or norethisterone-containing pills.

OCPs should not be used before epiphyseal closure. Caution is advised if cardiovascular risk factors are present.[135] Contraceptive pills should be avoided or used with caution in women with risk factors (e.g., smoking [especially if aged ≥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.[136]

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

Consider – metformin

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Consider –

metformin

Additional treatment recommended for SOME patients in selected patient group

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

For the specific goal of treating hyper-androgenism, metformin is best suited as add-on therapy to oral contraceptive pills (OCPs), anti-androgens, or OCPs plus anti-androgens. The Endocrine Society advises against using insulin-lowering drugs for the sole indication of treating hirsutism.[130] Metformin is associated with decreased testosterone and androstenedione levels and increased sex hormone-binding globulin levels, with limited evidence of improvement in hirsutism.[131][137][138][139] However, adding metformin might improve results compared with monotherapy or dual therapy.[131][139]

Limited evidence suggests that metformin may promote weight loss, particularly at higher doses (>1500 mg/day) and with longer duration of therapy (>8 weeks).[142] A meta-analysis of 51 studies concluded that metformin (alone or as adjuvant therapy) may improve acne scores.[140]

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]

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

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Consider –

mechanical hair removal or topical therapy

Additional 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.[143] 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.[144]

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

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

2nd line – anti-androgen

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2nd line –

anti-androgen

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 anti-androgen monotherapy as initial therapy for hirsutism because of its teratogenic potential (unless women are on adequate contraception).[130] For women who are not sexually active, have undergone permanent sterilisation, or are on long-acting reversible contraception, initial therapy with oral contraceptive pill or anti-androgens as monotherapy are both options.[130] 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 anti-androgens.[31][130]

Anti-androgens are androgen receptor blockers (e.g., spironolactone, cyproterone) or 5-alpha-reductase inhibitors (e.g., finasteride).

Anti-androgens (especially finasteride) should be avoided in pregnancy due to potential for ambiguous genitalia in male fetus. Anti-androgens should be used for at least 6 months before judging efficacy.[130] 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

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Consider –

metformin

Additional treatment recommended for SOME patients in selected patient group

The choice of agents to use is individualised, taking into account the clinical picture and preferences regarding 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

Consider –

mechanical hair removal or topical therapy

Additional 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.)

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks.[143] 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.[144]

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

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

2nd line – anti-androgen plus oral contraceptive pill

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2nd line –

anti-androgen plus oral contraceptive pill

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

In many cases, a combination of anti-androgen 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 anti-androgen.[130] All pharmacological therapies for hirsutism should be trialed at least 6 months before making changes in dose, switching to a new medication, or adding medication.[12][130]

Anti-androgens are androgen receptor blockers (e.g., spironolactone, cyproterone) or 5-alpha-reductase inhibitors (e.g., finasteride).

Contraceptive measures are advisable with anti-androgens given theoretical teratogenicity. Anti-androgens (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

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Consider –

metformin

Additional treatment recommended for SOME patients in selected patient group

The choice of agents to use is individualised, 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.[130] Metformin is associated with decreased testosterone and androstenedione levels and increased sex hormone-binding globulin levels, with limited evidence of improvement in hirsutism.[131][137][138][139] However, adding metformin might improve results compared with monotherapy or dual therapy.[131][139]

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

Consider –

mechanical hair removal or topical therapy

Additional 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.)

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks.[143] 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.[144]

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

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

3rd line – long-acting GnRH analogue plus oral contraceptive pill

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3rd line –

long-acting GnRH analogue 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 gonadotrophin-releasing hormone (GnRH) analogues (e.g., leuprorelin) yield profound suppression of gonadotrophins and suppress ovarian steroid synthesis.

Only to be used in severe or refractory ovarian hyper-androgenism.[130] GnRH agonists are best combined with oestrogen (oral contraceptive pills) to increase sex hormone-binding globulin and protect bones from resultant hypo-oestrogenaemia (women on GnRH without oestrogen replacement may lose 4% to 8% trabecular bone after 6 months) and avoid severe vasomotor symptoms.

With the oestrogen replacement, a progestin must also be given to protect the endometrium.[130]

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

Primary options

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

Consider – mechanical hair removal or topical therapy

Back

Consider –

mechanical hair removal or topical therapy

Additional 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.)

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks.[143] 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.[144]

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

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

with infrequent/reduced menstrual bleeding alone

1st line – weight loss

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1st line –

weight loss

Anovulatory women with polycystic ovary syndrome (PCOS) have chronic oestrogenisation 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 hyperinsulinaemia and thus hyper-androgenism).[64][80][81][82] Studies suggest dietary interventions, exercise, and/or behavioural coaching are effective for weight loss in PCOS, but no particular exercise or dietary composition (beyond caloric restriction) can be recommended over another.[64][78][85]

2nd line – oral contraceptive pill

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2nd line –

oral contraceptive pill

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

Among the older oral contraceptive pills (OCPs), ethinylestradiol/etynodiol is considered low androgenic and may be useful if a larger dose of oestrogen is needed. This higher-oestrogen-dose pill (ethinylestradiol/etynodiol) may be able to induce menses in women with persistent amenorrhoea. Persistent amenorrhoea may indicate endometrial atrophy resulting from hyper-androgenism (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 aged ≥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.[136]

Pills with these, 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.[132][133][134][147] Given this possible risk of venous thromboembolism with newer pills, some practitioners still prefer to use levonorgestrel- or norethisterone-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

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2nd line –

metformin

May be used to improve menstrual irregularity.

Limited evidence suggests that metformin may promote weight loss, particularly at higher doses (>1500 mg/day) and with longer duration of therapy (>8 weeks).[142]

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

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

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

Secondary options

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

with hyper-androgenic features plus infrequent/reduced menstrual bleeding

1st line – weight loss

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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 hyperinsulinaemia and thus hyper-androgenism).[64][80][81][82] Studies suggest dietary interventions, exercise, and/or behavioural 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][78][85]

Plus – oral contraceptive pill

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Plus –

oral contraceptive pill

Treatment recommended for ALL patients in selected patient group

Oral contraceptive pill (OCP: cyclic oestrogen plus a progestin) therapy modestly inhibits gonadotrophin secretion, and thus gonadotrophin-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 normalised after 3 months, the possibility of an androgen-secreting neoplasm should be considered.

OCPs with progestins with androgenic activity (e.g., levonorgestrel, norethisterone) should be avoided. Newer, less-androgenic progestins include desogestrel and norgestimate. Drospirenone is a spironolactone analogue with anti-androgenic and anti-mineralocorticoid properties. Pills with these newer, lower-androgenicity progestins may, however, confer a higher risk of venous thromboembolism than older pills, although a large prospective study found no such risk.[132][133][134][147] Given this possible risk of venous thromboembolism with newer pills, some practitioners still prefer to use levonorgestrel- or norethisterone-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.[135] OCPs should be avoided or used with caution in women with risk factors (e.g., smoking [especially if aged ≥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.[136]

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

Consider – metformin

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Consider –

metformin

Additional treatment recommended for SOME patients in selected patient group

The choice of agents to use is individualised, 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), anti-androgens, or OCPs plus anti-androgens. The Endocrine Society advises against using insulin-lowering drugs for the sole indication of treating hirsutism.[130] Metformin is associated with decreased testosterone and androstenedione levels and increased sex hormone-binding globulin levels, with limited evidence of improvement in hirsutism.[131][137][138][139] However, adding metformin might improve results compared with monotherapy or dual therapy.[131][139]

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

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Consider –

mechanical hair removal or topical therapy

Additional 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.)

Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks, and facial hair returns if eflornithine is discontinued.[143] 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.[144]

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

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

2nd line – anti-androgen plus oral contraceptive pill

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2nd line –

anti-androgen plus oral contraceptive pill

Weight loss should be encouraged in overweight women.

The choice of agents to use is individualised, 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 anti-androgens 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.

Anti-androgens are androgen receptor blockers (e.g., spironolactone, cyproterone) or 5-alpha-reductase inhibitors (e.g., finasteride).

Contraceptive measures are advisable with anti-androgens 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

Consider –

metformin

Additional treatment recommended for SOME patients in selected patient group

The choice of agents to use is individualised, taking into account the clinical picture and preferences regarding 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

Consider –

mechanical hair removal or topical therapy

Additional 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.)

For androgenetic alopecia, topical minoxidil treatment may be effective but must be used for several months.[144]

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

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

3rd line – long-acting GnRH analogue plus oral contraceptive pill

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3rd line –

long-acting GnRH analogue plus oral contraceptive pill

Weight loss should be encouraged in overweight women.

Long-acting gonadotrophin-releasing hormone (GnRH) analogues (e.g., leuprorelin) yield profound suppression of gonadotrophins and suppress ovarian steroid synthesis.

With the oestrogen replacement, a progestin must also be given to protect the endometrium.[130]

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

Primary options

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

Consider – mechanical hair removal or topical therapy

Back

Consider –

mechanical hair removal or topical therapy

Additional 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.)

For androgenetic alopecia, topical minoxidil treatment may be effective but must be used for several months.[144]

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

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

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Polycystic ovary syndrome

Treatment algorithm

with infertility and desiring fertility

weight loss

letrozole

Primary options

clomifene

Primary options

metformin

Primary options

dexamethasone

Primary options

metformin

Primary options

gonadotrophins

Primary options

Secondary options

metformin

Primary options

in vitro fertilisation

metformin

Primary options

laparoscopic ovarian drilling

not desiring current fertility

oral contraceptive pill

metformin

Primary options

mechanical hair removal or topical therapy

Primary options

anti-androgen

Primary options

Secondary options

metformin

Primary options

mechanical hair removal or topical therapy

Primary options

anti-androgen plus oral contraceptive pill

Primary options

Secondary options

metformin

Primary options

mechanical hair removal or topical therapy

Primary options

long-acting GnRH analogue plus oral contraceptive pill

Primary options

mechanical hair removal or topical therapy

Primary options

weight loss

oral contraceptive pill

metformin

Primary options

cyclic progestin

Primary options

Secondary options

weight loss

oral contraceptive pill

metformin

Primary options

mechanical hair removal or topical therapy

Primary options

anti-androgen plus oral contraceptive pill

Primary options

Secondary options

metformin

Primary options

mechanical hair removal or topical therapy

Primary options

long-acting GnRH analogue plus oral contraceptive pill

Primary options

mechanical hair removal or topical therapy

Primary options