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INTRODUCTION — 46,XX primary ovarian insufficiency (POI) is defined as the development of primary hypogonadism before the age of 40 years in women who have a normal karyotype. The presenting symptoms are similar to those of menopause. The condition was previously referred to as “premature menopause” and “premature ovarian failure.” The age-specific incidence of spontaneous POI is approximately 1 in 250 by age 35 years and 1 in 100 by age 40 years . In its fully developed form, it is associated with oligomenorrhea or amenorrhea, symptoms of estrogen deficiency, and gonadotropin levels in the menopausal range before age 40 years.
The management of women with spontaneous POI will be reviewed here. Turner syndrome (45,X0) and autoimmune POI, as well as other aspects of spontaneous (46,XX) POI, are reviewed separately. (See "Management of Turner syndrome" and "Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure)" and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure)".)
Informing the patient of the diagnosis — The first and most important step after making the diagnosis of spontaneous primary ovarian insufficiency (POI) is to inform the patient of the diagnosis in a sensitive and caring manner, provide accurate information, and offer referral to appropriate resources for emotional support. The most common words women use to describe their emotional state in the two hours after receiving the diagnosis are “devastated,” “shocked,” and “confused” .
Young women with POI are usually unprepared for the diagnosis, and the majority are unhappy with the manner in which they were informed . In one study of 100 women with POI, 71 percent were dissatisfied with how they were informed of their diagnosis . Specific areas of improvement suggested by women in the study included the need for clinicians to spend more time with the patient and provide more information about this condition.
It is best to schedule a return office visit to review the laboratory results when the diagnosis is suspected. It is also important to inform patients with 46,XX spontaneous POI that in some cases spontaneous remission can occur. Approximately 5 to 10 percent of women are able to become pregnant sometime after the diagnosis . (See 'Fertility' below.)
When first diagnosed with POI, patients often initially feel an urgent need to act immediately to achieve a pregnancy. At this point, it is helpful to stress the importance of first addressing other aspects of POI that may have adverse effects on their long-term health, such as emotional health, autoimmune endocrinopathies, and osteoporosis. (See "Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'Clinical features'.)
The diagnosis of POI brings with it the potential for development of related depression and anxiety disorders [2,5]. Data suggest that depression frequently occurs after the onset of menstrual irregularity but often precedes the diagnosis of POI . POI also has potential long-term sequelae, which are largely related to the associated endocrine deficiencies. (See 'Other endocrine issues' below and 'Emotional health/psychosocial support' below and 'Consequences of estrogen deficiency' below.)
APPROACH TO SUBSEQUENT MANAGEMENT
Consequences of estrogen deficiency — In the absence of exogenous estrogen replacement, women with primary ovarian insufficiency (POI) are at an increased risk for developing the following:
●Symptoms of estrogen deficiency, including vasomotor flushes, vaginal dryness, night sweats, fatigue, and mood changes, all of which generally respond to estrogen therapy.
●Osteopenia and osteoporosis, especially in young women who develop ovarian dysfunction before they achieve peak adult bone mass . Women with POI have a higher incidence of osteoporotic fractures .
In a large cross-sectional study of young women with 46,XX spontaneous POI as compared with control women, patients on average had 2 to 3 percent lower bone density in the lumbar spine, femoral neck, and total hip . The statistically significant modifiable risk factors for bone density below the expected range for age (Z-score <-2.0) were: more than one year delay in diagnosis of the estrogen deficiency, low vitamin D levels (<32 ng/mL), estrogen replacement non-adherence, low calcium intake, and lack of exercise. As compared with Caucasians, African American and Asian women were three to four times more likely to have bone density Z-scores <-2.0. On regression modeling, the racial disparity was not an independent predictor of low bone density and appeared to be related to a combined effect of several modifiable risk factors. Approximately 50 percent of women with 46,XX spontaneous POI had evidence of vitamin D deficiency as well as inadequate calcium intake, and 25 percent had no regular exercise program .
●Impaired endothelial function, increased cardiovascular morbidity and mortality, possibly related to endothelial dysfunction [10-15]. (See "Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Overview of cardiovascular risk factors in women", section on 'Hysterectomy' and "Overview of cardiovascular risk factors in women", section on 'Menopause'.)
Observational data suggest that early menopause may be associated with small increases in total mortality and mortality due to ischemic heart disease [13,16,17] and also possibly ischemic stroke . However, at this time, evidence is insufficient to recommend hormone replacement therapy for the sole purpose of preventing cardiovascular disease or stroke.
●Diminished sexual well-being [19-21].
●Impaired cognition – Some studies suggest that women under age 43 years who undergo bilateral oophorectomy and do not receive estrogen replacement are at increased risk for dementia and cognitive decline , but this risk has not been demonstrated for women with spontaneous POI . (See "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Cognitive function and neurologic disease'.)
Estrogen therapy — Unless there is an absolute contraindication to taking estrogen therapy, women with POI should receive estrogen therapy to prevent bone loss (in almost all cases with a progestin, as most of these patients have an intact uterus). In addition to estrogen therapy for prevention of bone loss, other important measures for bone health should be emphasized, including exercise, a healthy diet, adequate calcium and vitamin D intake, and avoiding smoking. (See "Overview of the management of osteoporosis in postmenopausal women".)
The current approach is to treat with a hormone replacement regimen that mimics normal physiology as closely as possible until the average age of natural menopause (age 50 to 51 years). (See 'Duration of treatment' below.)
Optimal replacement with sex steroids depends on whether the patient presents with primary or secondary amenorrhea. Girls or young women with primary amenorrhea in whom secondary sex characteristics have failed to develop should initially be given very low doses of estrogen (at first without a progestin) in an attempt to mimic gradual pubertal maturation. (See "Evaluation and management of primary amenorrhea" and "Management of Turner syndrome".)
The principal estrogen produced by the functioning premenopausal ovary is 17-beta-estradiol. Daily serum measurements of estradiol in regularly menstruating women indicate that the mean serum estradiol level averaged across the menstrual cycle is approximately 104 pg/mL (382 pmol/L) . Theoretically, hormone replacement for young women with POI should mimic normal ovarian function as much as possible. We start women on full replacement doses of estrogen such as transdermal estradiol or vaginal ring (100 mcg daily) [25-27]. This dose is also roughly equivalent to 2 mg of oral micronized estradiol, 1.25 mg of oral conjugated equine estrogen, or about 10 mcg of oral ethinyl estradiol. For women who do not like or do not tolerate transdermal or vaginal estradiol, we switch to oral estradiol.
Women with POI are young, and therefore most have an intact uterus and require a progestin to prevent estrogen-induced endometrial hyperplasia and carcinoma. Our first-line progestin is oral medroxyprogesterone acetate (10 mg daily for 12 days per calendar month). This regimen is based upon a three-year trial in 145 women with POI receiving 100 mcg/day of transdermal estradiol with 12 days/month of medroxyprogesterone acetate (10 mg) to maintain bone health . Compared to a control group of women with normal ovarian function, women with POI had lower pre-treatment bone mineral density (BMD) (lumbar spine and femoral neck), but after three years of hormone therapy, BMD increased at both sites and was similar to BMD measurements in the control group.
Providing estradiol by transdermal patch or vaginal ring has several potential advantages over oral estrogen preparations:
●It provides 17-beta-estradiol, which is structurally identical to ovarian 17-beta-estradiol.
●It avoids the first-pass effect on the liver (which is associated with increased production of clotting factors).
●It provides the replacement by steady infusion rather than by bolus.
●It permits measurement of serum estradiol levels by clinically available assays, should the need arise to adjust the replacement dose (although this is usually not necessary).
●It reduces the risk of venous thromboembolism compared with the oral route  and may be associated with a reduced risk of gallbladder disease (ie, cholecystitis, cholelithiasis, and cholecystectomy) .
Because most of these women have an intact uterus, an effective progestin regimen to fully reduce the risk of endometrial hyperplasia and carcinoma is critical . As noted above, our first-line progestin is medroxyprogesterone acetate 10 mg per day for the first 12 calendar days of each month [27,28].
Women should keep a menstrual calendar. If they miss a menstrual period, they should obtain a pregnancy test and stop the estrogen and progestin therapy if the test result is positive.
Women with POI should be informed that standard postmenopausal hormone therapy does not provide effective contraception. Since spontaneous ovarian activity may resume, some form of contraception may be required. (See 'Contraception' below.)
In one small randomized trial comparing the impact of oral contraceptives and physiologic sex-steroid replacement (transdermal estradiol/vaginal progesterone) on BMD and biochemical markers of bone resorption and formation, both treatments suppressed bone resorption markers . However, only the physiologic regimen increased bone formation markers and lumbar spine BMD Z-scores. Although further study is needed, this report suggests that administration of a physiologic regimen of transdermal estradiol with cyclic progestin may be better for skeletal health than pharmacologic doses of a combined estrogen-progestin regimen (ie, oral contraceptives).
When estradiol-progestin hormone therapy is prescribed, a cyclic regimen that will induce regular monthly menses allows easier recognition of the 5 to 10 percent potential for a spontaneous and unexpected pregnancy . These spontaneous pregnancies progress entirely normally in most cases and there appears to be no need for exogenous hormone supplementation during pregnancy.
Postmenopausal estrogen and progestin regimens, which are similar to those used for women with POI, are reviewed in detail separately. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Overview of approach'.)
Duration of treatment — Most patients are aware of the association between estrogen deficiency and osteoporosis, but they are also concerned about the potential risks of cardiovascular complications and breast cancer with long-term estrogen therapy that have been reported in older postmenopausal women .
It is important to stress to young women with POI that they differ from normally menopausal women in important ways with regard to the risk:benefit ratio of estradiol therapy. First, in the absence of estradiol replacement, they may be at greater risk for later coronary heart disease, overall mortality, cognitive decline, and dementia, presumably due to estradiol deficiency [10,12,13,15,22,34]. As an example, two studies suggest that women with POI have significant vascular endothelial dysfunction, which is restored to normal by estrogen therapy [12,15].
In addition, their baseline risks of cardiovascular disease and breast cancer are much lower than those for older postmenopausal women and therefore, the results of the Women's Health Initiative (WHI) are probably not clinically important until they reach approximately age 50 years, the average age at natural menopause.
Therefore, most experts agree that young women with POI should replace the hormones the ovary would normally provide at least until age 50 years [25,35,36]. The issue of postmenopausal hormone therapy after age 50 years is discussed in detail elsewhere. (See "Menopausal hormone therapy: Benefits and risks".)
Cancer survivors — Women with POI due to cytotoxic drugs or radiation therapy are often candidates for estradiol therapy. However, the decision to treat with estradiol depends upon the type of cancer (eg, estrogen is contraindicated in women with breast cancer, while estrogen is prescribed for women with Hodgkins lymphoma and ovarian insufficiency to preserve bone health and prevent cardiovascular disease). Like women with other causes of POI, the current approach is to continue estradiol until approximately age 50 years, the average age at natural menopause.
Other endocrine issues
Androgen deficiency — Women with POI may have some degree of androgen deficiency when compared with young women without ovarian insufficiency. In several studies, serum ovarian androgen concentrations (androstenedione and/or testosterone) were lower than age-matched women without ovarian insufficiency, but similar to those seen in older postmenopausal women [37-39]. In contrast, levels of dehydroepiandrosterone sulfate (DHEA-S), an adrenal androgen, were normal (although they would be expected to be low in women with coexisting primary adrenal insufficiency).
The clinical consequences of this decrease in ovarian androgens and the possible role of androgen therapy in women with POI have not been extensively studied. However, in one trial, 128 women with 46,XX POI on estrogen-progestin therapy were randomly assigned to 12 months of transdermal testosterone (150 mcg patch) or placebo . In spite of a significant increase in mean serum total testosterone concentrations in the testosterone group (52 and 50 ng/dL at 3 and 12 months, respectively), compared to placebo (16 and 18 ng/dL, respectively), there were no differences in quality of life, self-esteem, or mood symptoms between the two groups. The addition of testosterone to three years of estradiol-progestin therapy did not provide added benefit in BMD .
Potential side effects of androgen replacement include hirsutism and acne, and with oral preparations, dyslipidemia. We therefore suggest not using androgen replacement therapy in this population. However, in women with coexisting adrenal insufficiency, adrenal androgen therapy with dehydroepiandrosterone appears to be beneficial. A more detailed discussion of androgen production and therapy in women is found elsewhere. (See "Overview of androgen deficiency and therapy in women" and "Dehydroepiandrosterone and its sulfate".)
Autoimmune endocrinopathies — Young women with spontaneous POI are at increased risk for developing autoimmune adrenal insufficiency, a potentially fatal disorder . Generally, the development of disordered menses associated with POI precedes the development of symptomatic adrenal insufficiency by several years . If proper screening is performed, approximately 3 percent of women with spontaneous POI will be found to have asymptomatic autoimmune adrenal insufficiency .
As a screen for the presence of asymptomatic autoimmune adrenal insufficiency, serum anti-adrenal and anti-21 hydroxylase antibodies should be measured at the time of diagnosis of spontaneous POI in all women. Those with positive antibodies should be carefully evaluated for the presence of adrenal insufficiency. Women with adrenal autoimmunity detected by the presence of autoantibodies have a 50 percent risk of developing adrenal insufficiency . Those with positive antibodies should be evaluated for the presence of adrenal insufficiency by an 8 AM serum cortisol and plasma corticotropin (ACTH). Even if their adrenal function is found to be normal at initial evaluation, women with positive adrenal antibodies should be followed annually by these tests.
There are no available longitudinal data to inform on how to follow-up patients with negative tests for adrenal autoimmunity. If steroidogenic cell autoimmunity is the mechanism underlying the development of POI, one would expect, theoretically, that adrenal autoantibodies would be present. If adrenal autoantibodies are not present in a woman with POI, a reasonable strategy is to only repeat the testing as otherwise clinically indicated, (eg we do not suggest routine annual testing in those with negative antibody testing initially). It is important that all women with POI be educated regarding the symptoms of adrenal insufficiency and the need for further evaluation should these symptoms appear. (See "Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'Test for adrenal autoantibodies'.)
Young women with spontaneous POI also are at increased risk for developing autoimmune hypothyroidism  and should be routinely screened for this condition. (See "Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'Other autoimmune evaluation'.)
Sexual function — Most women who are taking a full replacement dose of physiologic estradiol score within the normal range on a validated measure of sexual function. Only 7 percent score below the second percentile on a composite sexual function score . As a group, compared with controls, women with 46,XX spontaneous POI score adversely with regard to sexual function [19,21].
Emotional health/psychosocial support — Psychosocial functioning is relatively poor compared with naturally menopausal women. The diagnosis of POI is emotionally traumatic for most women because it disrupts their life plans, hopes, and dreams with regard to raising a family. In one report, women with 46,XX POI (n = 100) had higher scores on depression, anxiety, and negative affect scales when compared with a group of control women (n = 60) . On regression analysis, factors that contributed significantly to these symptoms were illness uncertainty and stigma associated with the diagnosis. This diagnosis disrupts life plans and introduces symptoms of grief, anxiety, and depression. When the condition develops during adolescence, it is important to take a family systems approach to the evaluation [47,48].
As with any life-altering diagnosis, women with POI benefit from encouragement and support that helps them to regain a sense of control and confidence. The first step is to encourage the couple, when they are ready, to express their emotions about the diagnosis and validate those feelings. A simple and effective entrée into this discussion is: “Many patients with POI tell us that this is a very difficult diagnosis to accept emotionally” [5,49]. It is worth pointing out that coming to grips with emotions about this diagnosis is a gradual process and that the patient needs to give herself time and permission to work through these issues. Feelings of intense grief and loss for the biologic children they expected to have are normal for couples whose life plans included building a family. Discussions about the normal grieving process, the strains that the diagnosis might bring to their relationship, and the importance of open communication are also helpful.
Some young women mistakenly interpret the diagnosis of POI as an indication that they have become a menopausal woman who is “growing old overnight” . Symptoms of estrogen deficiency such as hot flashes and vaginal dryness can be interpreted as signs of premature aging. It is important to clarify that this is not the case.
Some women with spontaneous POI experience significant underlying anxiety and depression related to the diagnosis. It is therefore worth suggesting that patients with this diagnosis consider seeing a therapist with expertise in this area. In some cases, ongoing individual or group counseling is helpful .
Contraception — Women with POI should be informed that estradiol/progestin replacement therapy does not provide effective contraception. Since spontaneous ovarian activity may resume, some form of contraception may be required. There are anecdotal reports of women who have conceived while using oral contraceptives, perhaps due to the high follicle-stimulating hormone (FSH) levels characteristic in this condition .
The lead author of this topic review advises women to use a barrier method of contraception rather than an oral contraceptive . However, other clinicians suggest that oral contraceptives are a reasonable option in women who are concerned about the possibility of spontaneous ovulation and pregnancy [35,51]. Although there is no direct evidence for contraceptive efficacy in women with POI, there is indirect evidence of efficacy in perimenopausal women, another population with high serum gonadotropins and low fecundity .
Other contraceptive options are reviewed separately. (See "Contraceptive counseling and selection".)
Fertility — Approximately 75 percent of women with 46,XX spontaneous POI have potentially functional graafian follicles remaining in the ovary. Histologic and endocrinologic evidence supports a conclusion that inappropriate follicle luteinization is the most common pathophysiologic mechanism that prevents ovulation and pregnancy in these women [53,54]. (See 'Spontaneous ovulation' below.)
Although some women conceive without treatment, pregnancy rates are very low [3,55]. Other options include in vitro fertilization (IVF) with oocyte donation, embryo donation, and adoption (see "Oocyte donation for assisted reproduction"). Some women undergo ovulation induction, but data to support this approach are limited. Women who become pregnant by oocyte donation may have an increased risk of delivering infants who are small for gestational age and of having pregnancy-induced hypertension and postpartum hemorrhage [56-58], but these findings are controversial .
Spontaneous ovulation — In ultrasound studies of women with POI, follicular development occurs frequently, with evidence of follicle luteinization in many cases. Ovulation is infrequent, with about a 4 percent chance per month [53,60]. (See "Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'Clinical features'.)
Effect of estrogen therapy — It has been thought that exogenous estrogen might have a beneficial effect on ovulation and fertility, based upon the observation that some reports of pregnancy in POI have occurred in women taking estrogen [50,61].
However, in one report, exogenous administration of physiologic doses of estrogen did not appear to improve the spontaneous ovulation rate. This was illustrated in a trial of 37 women with POI randomly assigned to receive oral estradiol (2 mg/day) or no therapy for six weeks in a 12-week cross-over design . No effect of oral estradiol replacement was seen on mean ovarian volume, the number or size of new follicles, or ovulatory rates. Given the small size of this study, a possible benefit of estrogen cannot be excluded. Also, use of transdermal or transvaginal estradiol replacement might be more effective at improving follicle function due to the continuous rather than intermittent administration .
Gonadotropin therapy — Exogenous gonadotropin therapy has been studied as a potential strategy to improve ovulatory rates in women with POI, but it is ineffective [4,63]. Exogenous gonadotropins could theoretically exacerbate unrecognized autoimmune ovarian failure .
Combined with estrogen — Suppression of endogenous gonadotropin concentrations with pharmacologic doses of estrogen prior to gonadotropin therapy has been reported to improve ovulatory rates in some [65,66], but not all, studies . In the one randomized, placebo-controlled trial available, treatment with 150 mcg ethinyl estradiol/day for two weeks before and during stimulation with recombinant FSH, ovulatory rates were significantly higher in the estrogen group (32 percent, 8 of 25 women) when compared with the placebo group (0 of 25 ovulated) . Ovulation only occurred in women whose serum FSH concentrations were suppressed to ≤15 international units/L with estrogen. It is possible the improved ovulation rates in this study were related to suppression of luteinizing hormone (LH) levels and avoidance of inappropriate follicle luteinization .
With GnRH agonist — Suppression of endogenous gonadotropin concentrations with a gonadotropin-releasing hormone (GnRH) agonist prior to gonadotropin therapy does not appear to improve ovulatory rates [63,67,68].
Glucocorticoid therapy — Glucocorticoid therapy for treatment of suspected autoimmune ovarian failure, also unproven, carries the risk of iatrogenic Cushing's syndrome and osteonecrosis of the hip requiring joint replacement . (See "Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure)".)
Oocyte donation — Women with POI due to any cause are potential candidates for IVF with donor oocytes. In one report of 61 women with POI undergoing 90 treatment cycles, the cumulative chance of pregnancy after three cycles was approximately 90 percent . Success rates for this procedure depend primarily on the age of the oocyte donor. Women with Turner syndrome require careful cardiovascular evaluation before being considered for this therapy, as deaths from aortic dissection have been reported during pregnancy. (See "Oocyte donation for assisted reproduction" and "Management of Turner syndrome", section on 'Management of fertility and pregnancy'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Early menopause (primary ovarian insufficiency) (The Basics)")
●Beyond the Basics topics (see "Patient education: Early menopause (primary ovarian insufficiency) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The management of women with spontaneous primary ovarian insufficiency (POI) begins with informing the patient of the diagnosis in a sensitive and caring manner, providing accurate information about the diagnosis, and referring women with the condition to appropriate resources for emotional support. Young women with this disorder are unprepared for the diagnosis and, unfortunately, most are dissatisfied with the manner in which their healthcare providers delivered the information. (See 'Informing the patient of the diagnosis' above and 'Emotional health/psychosocial support' above.)
●We recommend estrogen-progestin replacement therapy for the restoration of bone mineral density (BMD) and the prevention of osteoporosis in women with POI (Grade 1B). This therapy provides the additional benefits of symptomatic control of vasomotor symptoms and vaginal dryness and, possibly, may also be of benefit in the prevention of coronary heart disease. (See 'Estrogen therapy' above.)
●For the anovulatory infertility associated with POI, we suggest not using ovulation induction drugs such as clomiphene citrate and gonadotropin therapy, as they have no proven benefit (Grade 2B). In patients who are comfortable with pursuing assisted reproductive technologies (ART), in vitro fertilization (IVF) with donor oocytes or donor embryos, given the high success rates, may be an option. (See 'Fertility' above.)
●The management of women with Turner syndrome (45, X0) is reviewed separately. (See "Management of Turner syndrome".)
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