There are also a number of genetic associations with POI (Table 13.2). Complete absence of an X chromosome causes Turner syndrome, which usually results in POI at a very young age, along with other somatic signs [7]. However, women with X chromosome microdeletions or Turner mosaicism may lack any phenotypic features of Turner syndrome yet still have POI. Karyotype screening is recommended to detect this condition. Mutations of a variety of genes have also been found to be related to POI, among them the FOXL2 gene (associated with blepharophimosis, ptosis, and epicanthus inversus) and Perrault syndrome (associated with deafness). Women who carry the permutation for the FMR1 (fragile X) gene are at high risk for POI and are also at risk of transmitting the full mutation to a male child, and therefore, screening of all women with POI for FMR1 is recommended; about 5 % will test positive [8].

Bone mineral density (BMD) may be compromised in women with POI. Women with POI have reduced bone mineral content compared to normally menstruating controls [9] and face many years of hypoestrogenemia, which further exacerbates the bone loss. Monitoring for low bone mass, for bone loss, and preventive treatment with hormones, when appropriate, is recommended. Although they provide about five times more estrogen than typical menopausal hormone therapy doses, oral contraceptives are not superior for preservation of bone mineral density, and thus either regimen can be considered bone sparing.

Cardiovascular disease (CVD) is more likely to occur in women who are hypogonadal during their reproductive years. Women with POI who do not take hormone replacement therapy may increase their risk of early-onset heart disease. There is some evidence that a POI diagnosis is associated with a greater risk of death from CVD [10].

Women with POI are at risk for depression. It is not clear whether depression precedes the diagnosis of POI or is partly due to the hormonal irregularities that accompany ovarian failure [11]. The clinician should be aware of the vulnerability of women with POI to depression and recommend treatment appropriately. Because this diagnosis afflicts women in their childbearing years, it often comes as a shock and a barrier to a much hoped-for pregnancy. Providing emotional support for women with POI is an important part of their care.

Fertility is often the overriding clinical concern when the diagnosis of POI is made. This can sometimes cause the clinician and the patient to lose sight of the need to provide holistic management of the patient. While the prognosis for natural fertility is overall poor, treatment-independent pregnancies are reported 5–10 % of women who have been diagnosed with POI [12]. In this respect, POI differs markedly from age-appropriate menopause. Assisted reproductive technology can be used to achieve pregnancy with great success when donor oocytes are utilized [13]. However, there is some evidence that aneuploidy is more common in pregnancies achieved spontaneously [14]. Because POI can be familial, use of sisters as known oocyte donors can be problematic unless careful genetic and phenotypic screening for ovarian reserve is performed [15]. Moreover, women with Turner syndrome and POI who attempt conception using donor oocytes are at high risk for catastrophic pregnancy outcomes due to silent aortic root disease or coarctation of the aorta [16].

Table 13.3 outlines diagnostic tests when suspecting POI. If fertility is not an overriding concern, long-term management of women with POI should include a thorough discussion of the risks and benefits of hormone therapy. Unlike a 50-year-old woman who is undergoing natural menopause, a woman who has POI in her 20’s or 30’s is deprived of estrogen at an abnormally young age, and therefore, “replacement” therapy is recommended to address not just symptoms of hypoestrogenism and improve quality of life but equally importantly to prevent premature cardiovascular and bone aging. Typical doses of estrogen used for women with age-appropriate menopause may be insufficient for full symptom control in women with POI [1]. Because the risks of harm of hormone replacement in women with POI appear to be minimal, clinicians should aim to supply enough hormone to eliminate menopausal symptoms of hot flashes and vaginal dryness.