Premature ovarian failure
- Overview
- Theory
- Diagnosis
- Management
- Follow up
- Resources
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
all patients
continuous combined hormone replacement therapy
The continuous combined regimen consists of both oestrogen and progestogen 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 amenorrhoea has elapsed. Cyclic regimens are preferred during this time to minimise 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
oestrogens, conjugated/medroxyprogesterone: 0.3 mg/1.5 mg orally once daily
OR
estradiol/norethisterone transdermal: 0.05 mg/0.14 mg per 24-hour patch twice weekly
OR
medroxyprogesterone: 2.5 mg orally once daily
-- AND --
conjugated oestrogens: 0.3 mg orally once daily
or
oestrogens, 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
counselling + supportive measures
Treatment recommended for ALL patients in selected patient group
Depression and low libido are common in women diagnosed with POF.[48]Liao KL, Wood N, Conway GS. Premature menopause and psychological well-being. J Psychosom Obstet Gynaecol. 2000 Sep;21(3):167-74. http://www.ncbi.nlm.nih.gov/pubmed/11076338?tool=bestpractice.com Patients and their partners will need assistance in coping personally and in their relationships. Support groups, individual counselling, or online resources are beneficial, especially in younger patients or patients with congenital problems.
Lifestyle modifications can help to 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 to modify changes in bone mineral density (BMD), as can weight-bearing exercise. Bisphosphonates, selective oestrogen 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.[53]Shapiro CL, Halabi S, Hars V, et al. Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. Eur J Cancer. 2011 Mar;47(5):683-9. http://www.ncbi.nlm.nih.gov/pubmed/21324674?tool=bestpractice.com
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.
vaginal oestrogen
Additional treatment recommended for SOME patients in selected patient group
Vaginal oestrogen 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.[39]European Medicines Agency. Four-week limit for use of high-strength estradiol creams. 4 October 2019 [internet publication]. https://www.ema.europa.eu/en/news/four-week-limit-use-high-strength-estradiol-creams Therefore, other vaginal formulations (e.g., conjugated oestrogen cream, estradiol intravaginal tablets and rings) may be preferred.
Primary options
oestrogens, 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 estradiol vaginalUse of estradiol 0.01% (100 micrograms/g) cream should be limited to a single treatment period of up to 4 weeks.[39]European Medicines Agency. Four-week limit for use of high-strength estradiol creams. 4 October 2019 [internet publication]. https://www.ema.europa.eu/en/news/four-week-limit-use-high-strength-estradiol-creams
testosterone supplementation
Additional treatment recommended for SOME patients in selected patient group
Androgen supplementation, in the form of oral or transdermal testosterone or prasterone (also known as dehydroepiandrosterone [DHEA]), can help to mitigate the effects of POF on bone health, muscle mass, fatigue, and low libido.[51]Panzer C, Guay A. Testosterone replacement therapy in naturally and surgically menopausal women. J Sex Med. 2009 Jan;6(1):8-18. http://www.ncbi.nlm.nih.gov/pubmed/19170830?tool=bestpractice.com
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.[52]Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014 Oct;99(10):3489-510. https://academic.oup.com/jcem/article/99/10/3489/2836272 http://www.ncbi.nlm.nih.gov/pubmed/25279570?tool=bestpractice.com
Primary options
testosterone transdermal: 2.5 to 7.5 mg/24-hour patch twice weekly
OR
testosterone topical: (1%) apply 5-10 g once daily
OR
prasterone vaginal: consult specialist for guidance on dose
OR
methyltestosterone: 10-50 mg orally once daily
treatment of associated autoimmune disease
Additional treatment recommended for SOME patients in selected patient group
It is important to treat associated autoimmune diseases.
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 amenorrhoea for <1 year, to minimise the risk of endometrial hyperplasia.
The cyclic sequential regimen is oestrogen daily for 21 days of the month, then no oestrogen for 7 days. Progestogen is added for days 7 to 21 and then stopped along with the oestrogen. A woman will have withdrawal bleeding on days 22 to 30.
The cyclic regimen is daily oestrogen. Progestogen 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.
counselling + supportive measures
Treatment recommended for ALL patients in selected patient group
Depression and low libido are common in women diagnosed with POF.[48]Liao KL, Wood N, Conway GS. Premature menopause and psychological well-being. J Psychosom Obstet Gynaecol. 2000 Sep;21(3):167-74. http://www.ncbi.nlm.nih.gov/pubmed/11076338?tool=bestpractice.com Patients and their partners will need assistance in coping personally and in their relationships. Support groups, individual counselling, or online resources are beneficial, especially in younger patients or patients with congenital problems.
Lifestyle modifications can also help to 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 to modify changes in bone mineral density (BMD), as can weight-bearing exercise. Bisphosphonates, selective oestrogen 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.[53]Shapiro CL, Halabi S, Hars V, et al. Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. Eur J Cancer. 2011 Mar;47(5):683-9. http://www.ncbi.nlm.nih.gov/pubmed/21324674?tool=bestpractice.com
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.
vaginal oestrogen
Additional treatment recommended for SOME patients in selected patient group
Vaginal oestrogen 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.[39]European Medicines Agency. Four-week limit for use of high-strength estradiol creams. 4 October 2019 [internet publication]. https://www.ema.europa.eu/en/news/four-week-limit-use-high-strength-estradiol-creams Therefore, other vaginal formulations (e.g., conjugated oestrogen cream, estradiol intravaginal tablets and rings) may be preferred.
Primary options
oestrogens, 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 estradiol vaginalUse of estradiol 0.01% (100 micrograms/g) cream should be limited to a single treatment period of up to 4 weeks.[39]European Medicines Agency. Four-week limit for use of high-strength estradiol creams. 4 October 2019 [internet publication]. https://www.ema.europa.eu/en/news/four-week-limit-use-high-strength-estradiol-creams
testosterone supplementation
Additional treatment recommended for SOME patients in selected patient group
Androgen supplementation, in the form of oral or transdermal testosterone or prasterone (also known as dehydroepiandrosterone [DHEA]), can help to mitigate the effects of POF on bone health, muscle mass, fatigue, and low libido.[51]Panzer C, Guay A. Testosterone replacement therapy in naturally and surgically menopausal women. J Sex Med. 2009 Jan;6(1):8-18. http://www.ncbi.nlm.nih.gov/pubmed/19170830?tool=bestpractice.com
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.[52]Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014 Oct;99(10):3489-510. https://academic.oup.com/jcem/article/99/10/3489/2836272 http://www.ncbi.nlm.nih.gov/pubmed/25279570?tool=bestpractice.com
Primary options
testosterone transdermal: 2.5 to 7.5 mg/24-hour patch twice weekly
OR
testosterone topical: (1%) apply 5-10 g once daily
OR
prasterone vaginal: consult specialist for guidance on dose
OR
methyltestosterone: 10-50 mg orally once daily
treatment of associated autoimmune disease
Additional treatment recommended for SOME patients in selected patient group
It is also important to treat associated autoimmune diseases.
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.[59]Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009 Feb 5;360(6):606-14. http://www.ncbi.nlm.nih.gov/pubmed/19196677?tool=bestpractice.com
There are currently no known markers or therapies that are associated with restoration of ovarian function and therefore fertility.[59]Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009 Feb 5;360(6):606-14. http://www.ncbi.nlm.nih.gov/pubmed/19196677?tool=bestpractice.com
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 fertilise the donated oocyte. Donor oocyte treatment is a difficult and stressful option for many couples, and expert counselling is recommended.
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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