Approach
Management should attempt to modify both physical and psychological consequences. Treatment involves hormone replacement therapy and protection of bone health. It is also important to treat associated autoimmune diseases. Fertility and childbearing should also be discussed, with an emphasis on oocyte donation or adoption if desired.
Hormone replacement therapy (HRT)
This is the mainstay of treatment, which is recommended until the average age of natural menopause (approximately 50-52 years).[37][38] HRT protects against symptoms of oestrogen deficiency, osteoporosis, possibly cardiovascular complications, and sexual dysfunction. Standard HRT can be initiated at low doses to enhance compliance. Oral or transdermal formulations are available. In patients with an intact uterus, progestogens must be given to reduce the risk of endometrial hyperplasia and/or cancer.[37]
There are four common combination regimens of HRT:
The continuous combined regimen is both oestrogen and progestogen daily.
The combined cyclic regimen is both oestrogen and progestogen for days 1 to 25 of the month followed by withdrawal bleeding days 26 to 31.
The cyclic sequential regimen is oestrogen daily for 21 days of the month, then no oestrogen for 7 days. Progestogens 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.
The continuous combined regimen is the easiest to follow and involves no period, so it is preferred by most women. However, it is not recommended until 1 year of amenorrhoea has elapsed. Cyclical 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 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. Individual patients will find different HRT regimens that are acceptable to them.
Vaginal oestrogen can be considered adjunctively for complaints of vaginal dryness or irritation associated with atrophy. Various vaginal oestrogen 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) HRT. This formulation should not be used in patients already on HRT.[39] Therefore, other vaginal oestrogen formulations (e.g., conjugated oestrogen cream, estradiol intravaginal tablets and rings) may be preferred.
Many women with POF are anxious about the possibility of an increased risk of developing breast cancer if they use HRT. They should be reassured that the evidence that associates HRT with breast cancer is derived from studies of women who used HRT beyond the age of natural menopause. In these women, the increased risk of breast cancer is related to duration of treatment with HRT (beyond the age of natural menopause), and likely recedes after treatment stops.[40][41][42] HRT for women with POF is physiological in that it is a true replacement of a hormone that is normally secreted until the age of 50 years, so the breast is not exposed to oestrogen at an abnormal time of the woman's life if treatment is discontinued at 50 years.
Although firm evidence is lacking, it seems prudent to gradually reduce the dose of HRT over a 6- to 12-month period at the age of 50 years, rather than stopping treatment immediately, to reduce symptoms of oestrogen withdrawal. One meta-analysis of prospective studies found HRT use for more than 1 year in postmenopausal women to be associated with an increased risk of breast cancer.[43] Risk increased with longer duration of HRT use, and persisted for more than 10 years after HRT was stopped. Risk was higher with combined oestrogen-progestogen compared with oestrogen-only preparations, but there was no increased risk with topical vaginal oestrogens. Advice remains unchanged: HRT should be used for the shortest time it is needed, and patients should be vigilant for signs of breast cancer and encouraged to attend regular breast cancer screening.[44][45][46] The risks and benefits of HRT should be discussed with patients during shared decision-making before commencing HRT.[40][47]
Psychological factors
The diagnosis of POF can be psychologically devastating, especially in women who have not completed their family. Depression and feelings of low libido are common in women diagnosed with POF.[48] 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.
Testosterone supplementation
The ovaries are endocrine organs that also produce androgens, and levels of androgens are known to be lower in women with premature menopause.[49][50] The potential implications of hypoandrogenism in these women remain to be elucidated.[50] 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] There are multiple formulations as creams, gels, patches, and tablets. However, testosterone supplementation is controversial as randomised trials 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]
Supportive measures
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] Smoking should be discouraged, as it contributes to bone loss.
A Cochrane review of 43 randomised controlled trials involving phyto-oestrogens found that there was a large placebo effect (from 1% to 59%) in most of the trials.[54] This, and other reviews, have found no conclusive evidence that phyto-oestrogens, including isoflavones, are effective for the management of vasomotor symptoms.[55][54][56]
Family planning
Women with POF should be counselled that ovarian function can fluctuate and it is not always irreversible. Therefore, ovulation and even pregnancy can occur. Spontaneous pregnancy rates as high as 5% to 10% are often cited, with no higher rates of pregnancy loss than the general population.[57][58] HRT is not contraceptive, but should be stopped if a pregnancy test is positive. Women who wish to conceive should avoid taking bisphosphonates as the effects on the fetus are unknown.[59]
There are currently no known therapies that can restore ovarian function and therefore fertility.[59] 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.
If a woman does not wish to conceive, then it is advised that she uses a barrier method or an intrauterine device because spontaneous ovulation may still occur.[59]
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