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

all patients

1st line – continuous combined hormone replacement therapy

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ACUTE
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all patients
1st line – 

continuous combined hormone replacement therapy

The continuous combined regimen consists of both estrogen and progestin given daily with no break. It is the easiest regimen to follow and involves no menstrual bleeds. However, it is not recommended until 1 year of amenorrhea has elapsed. Cyclic regimens are preferred during this time, to minimize the risk of endometrial hyperplasia.

If the woman has breakthrough bleeding after the first 9 months on the continuous combined regimen, it may be advisable to switch to a combined cyclic so she can have predictable periods.

Doses should be started low and increased according to response.

Primary options

estrogens, conjugated/medroxyprogesterone: 0.3 mg/1.5 mg orally once daily

OR

estradiol/norethindrone acetate transdermal: 0.05 mg/0.14 mg per 24-hour patch twice weekly

OR

medroxyprogesterone: 2.5 mg orally once daily

-- AND --

estrogens, conjugated: 0.3 mg orally once daily

or

estrogens, esterified: 0.625 mg orally once daily

or

estradiol transdermal: dose depends on brand of patch, spray, or gel; consult product literature for guidance on dose

Plus – counseling + supportive measures

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ACUTE
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all patients
Plus – 

counseling + supportive measures

Treatment recommended for ALL patients in selected patient group

Depression and low libido are common in women diagnosed with POF.[49] Patients and their partners will need assistance in coping personally and in their relationships. Support groups, individual counseling, or online resources are beneficial, especially in younger patients or patients with congenital problems.

Lifestyle modifications can help protect bone health. Recommendations for women with premature menopause are similar to national standards for postmenopausal women. Adequate calcium and vitamin D intake can help modify changes in bone mineral density (BMD), as can weight-bearing exercise. Bisphosphonates, selective estrogen receptor modulators, or other treatments for osteoporosis may be required. Third-generation bisphosphonates have been shown to be effective in preserving BMD in women with chemotherapy-induced early menopause, and should optimally be commenced at the time of initiation of chemotherapy.[54]

Smoking should be discouraged, as it contributes to bone loss.

Hormone replacement therapy is not contraceptive, and contraception should be provided to women who do not want to be exposed to any chance of pregnancy.

Consider – vaginal estrogen

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ACUTE
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all patients
Consider – 

vaginal estrogen

Treatment recommended for SOME patients in selected patient group

Vaginal estrogen can be considered for complaints of vaginal dryness or irritation associated with atrophy.

Various vaginal formulations are available, including a vaginal tablet, vaginal rings, and vaginal creams. In October 2019, the European Medicines Agency recommended limiting the use of high-strength estradiol vaginal creams (containing estradiol 100 micrograms/g or 0.01%) to a single treatment period of up to 4 weeks due to the risk of adverse effects usually associated with systemic (oral or transdermal) hormone replacement therapy (HRT). This formulation should not be used in patients already on HRT.[40] Therefore, other vaginal formulations (e.g., conjugated estrogen cream, estradiol intravaginal tablets and rings) may be preferred.

Primary options

estrogens, conjugated vaginal: (0.625 mg/g cream) insert 0.5 to 2 g into the vagina once daily for 21 days, followed by no treatment for 7 days, then repeat; or insert 0.5 g into the vagina twice weekly

OR

estradiol vaginal: (intravaginal tablets) 10 micrograms (1 tablet) into the vagina once daily for 2 weeks, followed by 10 micrograms (1 tablet) twice weekly thereafter; (intravaginal ring) 1 ring (7.5 micrograms/24 hours or 50-100 micrograms/24 hours) inserted into the vagina and replaced every 3 months, dose depends on brand used; (0.01% or 100 micrograms/g cream) insert 2-4 g (200-400 micrograms) into the vagina once daily for 1-2 weeks, then taper dose gradually over 1-2 weeks to maintenance dose of 1 g (100 micrograms) once to three times weekly (3 weeks on, 1 week off)

More

Consider – testosterone supplementation

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ACUTE
|
all patients
Consider – 

testosterone supplementation

Treatment recommended for SOME patients in selected patient group

Androgen supplementation, in the form of oral or transdermal testosterone or dehydroepiandrosterone (DHEA), can help mitigate the effects of POF on bone health, muscle mass, fatigue, and low libido.[52]

There are multiple formulations as creams, gels, transdermal patches, and tablets.

However, testosterone supplementation is controversial as efficacy studies are lacking. Testosterone therapy should only be initiated by clinicians experienced in its use because of the lack of long-term safety data. Careful monitoring and follow-up are crucial.[53]

Primary options

testosterone transdermal: 2.5 to 7.5 mg/24-hour patch twice weekly

OR

testosterone transdermal: (1%) apply 5-10 g once daily

OR

dehydroepiandrosterone: 50 mg orally once daily

OR

methyltestosterone: 10-50 mg orally once daily

Consider – treatment of associated autoimmune disease

Back
ACUTE
|
all patients
Consider – 

treatment of associated autoimmune disease

Treatment recommended for SOME patients in selected patient group

It is also important to treat associated autoimmune diseases.

2nd line – cyclic hormone replacement therapy

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ACUTE
|
all patients
2nd line – 

cyclic hormone replacement therapy

If the woman has breakthrough bleeding after the first 9 months on the continuous combined regimen, it may be advisable to switch to the combined cyclic regimen so she can have predictable periods. Alternative options are the cyclic sequential regimen or the cyclic regimen, both of which have withdrawal bleeding. Cyclic regimens are also preferred if the woman has had amenorrhea for <1 year, to minimize the risk of endometrial hyperplasia.

The cyclic sequential regimen is estrogen daily for 21 days of the month, then no estrogen for 7 days. Progestin is added for days 7 to 21 and then stopped along with the estrogen. A woman will have withdrawal bleeding on days 22 to 30.

The cyclic regimen is daily estrogen. Progestin is added days 1 to 14, and the woman will have withdrawal bleeding during the middle of the month.

Many products and formulations are available.

Doses should be started low and increased according to response.

Plus – counseling + supportive measures

Back
ACUTE
|
all patients
Plus – 

counseling + supportive measures

Treatment recommended for ALL patients in selected patient group

Depression and low libido are common in women diagnosed with POF.[49] Patients and their partners will need assistance in coping personally and in their relationships. Support groups, individual counseling, or online resources are beneficial, especially in younger patients or patients with congenital problems.

Lifestyle modifications can also help protect bone health. Recommendations for women with premature menopause are similar to national standards for postmenopausal women. Adequate calcium and vitamin D intake can help modify changes in bone mineral density (BMD), as can weight-bearing exercise. Bisphosphonates, selective estrogen receptor modulators, or other treatments for osteoporosis may be required. Third-generation bisphosphonates have been shown to be effective in preserving BMD in women with chemotherapy-induced early menopause, and should optimally be commenced at the time of initiation of chemotherapy.[54]

Smoking should be discouraged, as it contributes to bone loss.

Hormone replacement therapy is not contraceptive, and contraception should be provided to women who do not want to be exposed to any chance of pregnancy.

Consider – vaginal estrogen

Back
ACUTE
|
all patients
Consider – 

vaginal estrogen

Treatment recommended for SOME patients in selected patient group

Vaginal estrogen can be considered for complaints of vaginal dryness or irritation associated with atrophy.

Various vaginal formulations are available, including a vaginal tablet, vaginal rings, and vaginal creams. In October 2019, the European Medicines Agency recommended limiting the use of high-strength estradiol vaginal creams (containing estradiol 100 micrograms/g or 0.01%) to a single treatment period of up to 4 weeks due to the risk of adverse effects usually associated with systemic (oral or transdermal) hormone replacement therapy (HRT). This formulation should not be used in patients already on HRT.[40] Therefore, other vaginal formulations (e.g., conjugated estrogen cream, estradiol intravaginal tablets and rings) may be preferred.

Primary options

estrogens, conjugated vaginal: (0.625 mg/g cream) insert 0.5 to 2 g into the vagina once daily for 21 days, followed by no treatment for 7 days, then repeat; or insert 0.5 g into the vagina twice weekly

OR

estradiol vaginal: (intravaginal tablets) 10 micrograms (1 tablet) into the vagina once daily for 2 weeks, followed by 10 micrograms (1 tablet) twice weekly thereafter; (intravaginal ring) 1 ring (7.5 micrograms/24 hours or 50-100 micrograms/24 hours) inserted into the vagina and replaced every 3 months, dose depends on brand used; (0.01% or 100 micrograms/g cream) insert 2-4 g (200-400 micrograms) into the vagina once daily for 1-2 weeks, then taper dose gradually over 1-2 weeks to maintenance dose of 1 g (100 micrograms) once to three times weekly (3 weeks on, 1 week off)

More

Consider – testosterone supplementation

Back
ACUTE
|
all patients
Consider – 

testosterone supplementation

Treatment recommended for SOME patients in selected patient group

Androgen supplementation, in the form of oral or transdermal testosterone or dehydroepiandrosterone (DHEA), can help mitigate the effects of POF on bone health, muscle mass, fatigue, and low libido.[52]

There are multiple formulations as creams, gels, transdermal patches, and tablets.

However, testosterone supplementation is controversial as efficacy studies are lacking. Testosterone therapy should only be initiated by clinicians experienced in its use because of the lack of long-term safety data. Careful monitoring and follow-up are crucial.[53]

Primary options

testosterone transdermal: 2.5 to 7.5 mg/24-hour patch twice weekly

OR

testosterone transdermal: (1%) apply 5-10 g once daily

OR

dehydroepiandrosterone: 50 mg orally once daily

OR

methyltestosterone: 10-50 mg orally once daily

Consider – treatment of associated autoimmune disease

Back
ACUTE
|
all patients
Consider – 

treatment of associated autoimmune disease

Treatment recommended for SOME patients in selected patient group

It is also important to treat associated autoimmune diseases.

Plus – donor oocyte + embryo transfer

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ACUTE
|
all patients
|
pregnancy desired
Plus – 

donor oocyte + embryo transfer

Treatment recommended for ALL patients in selected patient group

Patients who are hoping to conceive should be encouraged to keep a menstrual calendar and to carry out a pregnancy test if a period is late.

Hormone replacement therapy should be stopped if a pregnancy test is positive.

Women who are hoping to get pregnant should avoid taking bisphosphonates, as the effects on the fetus are unknown.[60]

There are currently no known markers or therapies that are associated with restoration of ovarian function and therefore fertility.[60]

The only effective treatment for infertility in women with POF is use of donor oocytes in the context of IVF treatment, using the husband/partner's sperm to fertilize the donated oocyte. Donor oocyte treatment is a difficult and stressful option for many couples, and expert counseling is recommended.

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Choose a patient group to see our recommendations

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

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