Premature Ovarian Insufficiency

Abstract

Natural menopause typically occurs between the ages of 46 to 55 years. Premature ovarian insufficiency or premature menopause refers to compromised ovarian follicular activity, occurring spontaneously or because of medical interventions, prior to the age of 40 years. The premature loss of estrogen leads to bothersome menopause symptoms and predisposes the women to multiple long-term health risks including a higher mortality risk. Hormone replacement therapy used until the natural age of menopause can help manage the symptoms effectively and can mitigate the long-term risk of estrogen deprivation to some extent. However, hormone replacement therapy is underutilized in this population due to the inappropriate extrapolation of potential risks that have been demonstrated with hormone therapy use in women after natural menopause. There is a large unmet need for educating patients and providers regarding the impact of premature ovarian insufficiency and the compelling need for its appropriate management.

INTRODUCTION

Premature ovarian insufficiency (POI) refers to hypergonadotropic hypogonadism due to loss of ovarian follicular activity prior to the age of 40 years. It results in a decline in or a loss of fertility and female reproductive hormones, particularly estrogen. The term “premature” has been coined to contrast this entity with natural menopause, which typically occurs between the ages of 46 to 55 years. The cut-off age of 40 years is more than 2 standard deviations below the average age of natural menopause (~51 years). POI was previously referred to as “premature ovarian failure”. The latter terminology has fallen out of favor for two main reasons. First, the term “failure” conveys a sense of permanency, which is not always the case with POI. Up to 10% of women with spontaneous POI may have a recovery of their ovarian function, albeit brief, which may even result in a pregnancy.¹ Secondly, the word “failure” also conveys a negative connotation, which can have an adverse psychological impact on women affected by the condition.

The prevalence of POI was previously estimated to be around 1%,² but a recent meta-analysis reported a prevalence rate of 3.7% with even higher rates in countries with a medium or low Human Development Index.³ Premature estrogen deprivation resulting from POI has multiple adverse long-term consequences for a woman’s health, including an increased risk of coronary artery disease, osteoporosis, dementia, diabetes, dyslipidemia, and multiple other chronic health conditions that contribute to multimorbidity accumulation and accelerated aging.^1,4,5 In addition, the psychological impact of loss of fertility at a young age can be tremendous. Oftentimes, the diagnosis of POI is delayed, adding further to the psychological trauma associated with this diagnosis. Women with POI therefore not only need appropriate medical management, which includes hormone replacement therapy (HRT), there is an important role for psychological support. Loss of ovarian function, particularly due to bilateral oophorectomy, often results in decline in androgen levels and associated sexual dysfunction. Therefore, testosterone replacement is necessary as well for some women. Hormone replacement therapy is underutilized in women with POI, given the inappropriate and unfair extrapolation from the potential risks associated with hormone therapy use in women after natural menopause. There is a large unmet need for educating patients and providers regarding appropriate management of women with POI. This purpose of this concise review is to provide updated summary recommendations for evaluation and management of POI. These recommendations are based on recently published studies and reviews on the topic (mostly within the last 5 years) and in some places, expert opinion, due to the lack of evidence and consensus guidelines in the respective areas.

ETIOLOGY OF PREMATURE OVARIAN INSUFFICIENCY

POI is a result of premature loss of the ovarian follicle pool. Multiple factors can lead to the premature destruction or atresia of the ovarian follicles.¹ These can be broadly classified into induced and spontaneous causes. The spontaneous causes include autoimmunity, genetic causes, toxin exposures and idiopathic causes^1,6,7 (Table 1). While the etiology is typically obvious in the iatrogenic causes, it may not always be possible to delineate the specific cause in women with spontaneous POI, and often a combination of these factors is at play. For example, a genetic predisposition towards accelerated follicular atresia may be hastened by one of the other factors⁸. Also, POI may very well occur as part of biological aging in some women. There is evidence to suggest that epigenetic aging can originate early, even within weeks after conception in female fetuses.⁹ Determining the specific etiology may be particularly important in genetic causes, for the purposes of testing and counseling of other family members. The etiology remains unknown in 70–90% of women with spontaneous POI.¹⁰ Although these patients are classified as having idiopathic POI, many of these women likely have an undiagnosed genetic cause.

Table 1:

Causes of premature ovarian insufficiency

Induced	Spontaneous
Iatrogenic Surgeries and procedures: Bilateral oophorectomy, bilateral cystectomy, hysterectomy, other pelvic surgeries, uterine artery embolization Chemotherapy and stem cell transplantation External beam and intracavitary radiation	Idiopathic No cause identified (70–90% of cases) Genetic X-linked: Monosomy, trisomy, deletions, translocations, Fragile X Autosomal dominant Autoimmunity
Environmental Toxic Exposures Polycyclic aromatic hydrocarbons (cigarette smoke) Phthalates and bisphenol-A (plastic production)	Infections Mumps, HIV1, tuberculosis, malaria, CMV2, varicella and shigella

^1:Human Immunodeficiency Virus

^2:Cytomegalovirus

Iatrogenic causes

Damage to the ovaries may result from surgery, chemotherapy, or radiation therapy to the pelvic organs. Culprit surgeries include bilateral oophorectomy, ovarian cystectomy, other pelvic surgeries and procedures, including hysterectomy and uterine artery embolization that can impair ovarian blood supply and therefore lead to ovarian insufficiency.¹ The risk for chemotherapy associated ovarian insufficiency and the potential for recovery from it depends on the chemotherapeutic agent(s) utilized, age at treatment, and the baseline ovarian reserve.^11,12 Women who receive anthracyclines and alkylating agents, and those who receive allogeneic stem cell transplantation are at the highest risk.¹³ With the rise in cancer survivorship, the proportion of women with iatrogenic POI has increased over the years.¹⁴

Genetic causes

Family history of POI or early menopause may be demonstrable in up to one-third of women with idiopathic POI, suggesting an inherited cause.¹⁵ The implicated genes mostly involve the X chromosome, and less frequently the autosomal chromosomes. The most common chromosomal abnormality in POI is Turner syndrome (XO). It is a result of complete or partial loss of one of the X chromosomes.¹⁶ Turner syndrome mosaicism can result in less severe forms of POI, with potential for pregnancy.¹⁷ The most common genetic abnormality in POI is a premutation in the fragile X mental retardation (FMR1) gene. It affects one in 250 women, and results in an increase in the number of CGG trinucleotide repeats in the gene on the X chromosome.¹⁸ Presence of 200 or higher repeats in males results in the full-blown syndrome of mental retardation and autism. Presence of 55–200 repeats (premutation) predicts a 20% chance of developing POI.¹⁹ Multiple autosomal gene mutations have also been implicated in POI, with some identified mutations, and the others being candidate genes at best.²⁰

Autoimmune causes

Women with spontaneous POI have a higher prevalence of autoimmune conditions including adrenal insufficiency, Hashimoto’s thyroiditis, type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease. POI also occurs in women with the autoimmune polyglandular endocrinopathies. Therefore, an autoimmune mechanism for POI seems plausible. However, a specific immune marker for ovarian autoimmunity is not available. Ovarian antibody testing has a high rate of false positivity.²¹ In women who have other autoimmune conditions, if no other cause for ovarian insufficiency is forthcoming, an autoimmune cause is likely, but it cannot be established based on laboratory testing. At the same time, given the association with autoimmune conditions, women with spontaneous POI should be screened for other autoimmune conditions, particularly adrenal-directed autoimmunity and Hashimoto’s thyroiditis.²⁰

CLINICAL FEATURES AND LONG-TERM HEALTH RISKS OF PREMATURE OVARIAN INSUFFICIENCY

1. Clinical presentation

The women with POI typically present with secondary amenorrhea or oligomenorrhea, infertility or subfertility, and symptoms of estrogen deficiency. However, there is considerable variability in the presenting symptoms, particularly in the women with spontaneous POI. The fluctuating levels of ovarian hormones can result in intermittent symptoms in the early stages of POI. This variability and inconsistency in presenting features can unfortunately lead to a delay in the diagnosis of POI, and many affected women experience symptoms for months before a diagnosis is made. When present, the typical symptoms of estrogen deficiency mirror those experienced by women around natural menopause, including hot flashes, night sweats, sleep disturbances, mood changes, anxiety, cognitive complaints, and sexual dysfunction. However, in general, the symptoms tend to be more severe in the young women with POI compared to women experiencing natural menopause. Additionally, given the more abrupt cessation of ovarian function, women with iatrogenic POI may experience even more dramatic and severe symptoms with a more prominent psychosocial component.^22–24

Psychological impact of POI

POI is a life-changing diagnosis for women with a tremendous psychological burden. The psychosocial symptoms are often disproportionately higher in this patient population in comparison to the women experiencing psychological symptoms in the context of natural menopause.¹ Infertility is a major contributor to the psychological burden,²⁴ but other potential culprits include the psychological trauma imposed by the etiology of POI (for example, cancer), compromised physical wellbeing related to severe menopause symptoms, impaired body image and sense of femininity, poor self-esteem and self-confidence, sexual dysfunction in the context of a young age, and perception of poor social support. As a result, women with POI demonstrate higher levels of depression and stress, lower life satisfaction, poorer quality of life and overall worse mental health when compared to women experiencing natural menopause.^25–27 Therefore, the psychological wellbeing of women with POI should be specifically and diligently assessed and addressed.

2. Sexual dysfunction in women with POI

Sexual function in women with POI is often impacted significantly because of both biologic and psychologic factors.²⁸ Menopause-related symptoms described earlier in the review can compromise a woman’s overall wellbeing with detrimental effects on her sexual function. Moreover, estrogen deficiency also results in genitourinary changes that adversely impact sexual function. These include vaginal dryness, loss of vaginal elasticity, pelvic floor tension, ultimately resulting in dyspareunia and avoidance of sexual activity. Women with POI, particularly those with prior bilateral oophorectomy, may have a significant decline in their androgen levels.^29,30 Because androgens are thought to have a supportive role in female sexual function, the relative androgen deficiency in women with POI can result in sexual dysfunction.³¹ The compromised psychological wellbeing in a woman with POI as described above can also interfere with her ability to have a satisfying intimate relationship.³²

3. Long-term health risks of POI

In addition to bothersome symptoms, there is strong evidence to support that premature estrogen deprivation in women with POI results in substantial long-term health risks, multimorbidity accumulation, accelerated aging and premature death.^{1,4,20, 33} Long-term hypoestrogenism resulting from POI increases the risk for coronary artery disease, stroke, visceral adiposity, insulin resistance, dyslipidemia, diabetes, osteoporosis, cognitive impairment, and Parkinson’s disease.^1,4,34–36

LABORATORY EVALUATION OF PREMATURE OVARIAN INSUFFICIENCY

1. Establishing the diagnosis of POI

The diagnosis of a low ovarian reserve in a woman with amenorrhea or oligomenorrhea requires laboratory confirmation. Estradiol levels are not helpful unless they are very low. Moreover, estradiol levels can fluctuate in women with spontaneous POI, particularly in the early stages of the disease, making them unreliable for the diagnosis. Most guidelines recommend the use of 2 FSH tests, 4–6 weeks apart for confirmation of POI.^1,37–40 The diagnostic cut-offs vary based on the guideline used, but the most widely accepted threshold is >40IU/L.¹ The National Institute for Health and Care Excellence and the European Society of Human Reproduction and Embryology guidelines suggest lower diagnostic thresholds of >30 IU/L⁴⁰ and >25 IU/L³⁷, respectively.

Anti-müllerian hormone (AMH) has been considered the best marker of diminished ovarian reserve because it is produced by the developing antral follicles in the ovaries. A compromised ovarian follicular pool results in a low AMH level, but diagnostic cut-offs for POI have not been established, and AMH can be undetectable long before a woman becomes menopausal. Moreover, the ultrasensitive assays are expensive and not universally available. These factors preclude the use of AMH as a diagnostic tool for POI in general.¹ However, it can be a useful tool for predicting the development of ovarian insufficiency in iatrogenic settings like chemotherapy or radiation use.⁴¹ It can also be a useful predictor of ovarian response to gonadotropin therapy in assisted reproduction protocols.⁴²

Antral follicular count (AFC) is expected to be low in POI and it can be assessed with a transvaginal ultrasound.

2. Other diagnostic tests

Once the diagnosis of POI is confirmed, or is reasonably certain, genetic assessment should be offered to all women, particularly those younger than 30 years of age at the time of symptom onset, those with a family history of POI, and those with learning disabilities. The testing involves a karyotype assessment and FMR1 gene premutation testing. Given the frequent co-existence of POI and autoimmune conditions, testing for common autoimmune associations, including adrenal insufficiency and Hashimoto’s thyroiditis, is recommended. All women diagnosed with POI should be tested for 21-hydroxylase antibody, thyroid peroxidase antibody and TSH. If the 21-hydroxylase antibody is positive, adrenal function should be assessed.²¹

3. Tests of metabolic and bone health

Given the long-term impact of POI on cardiometabolic and bone health, women diagnosed with this condition should have a baseline assessment of metabolic parameters with a fasting glucose, lipid profile, HbA1c and a bone density assessment with a dual-energy X-ray absorptiometry (DXA) scan. While it may be ideal to repeat the metabolic tests annually, there are no consensus guidelines, and frequency of testing can be individualized based on a woman’s risk factors and cost considerations. Similarly, the frequency of bone density assessment is dictated by the results of the baseline bone density and the presence of other risk factors for low bone mass.^1,20

MANAGEMENT OF WOMEN WITH PREMATURE OVARIAN INSUFFICIENCY

1. General principles

Given the significant impact of POI on multiple aspects of a woman’s health, including her long-term health risk, its management must be multifaceted with a multidisciplinary focus whenever feasible. The treatment goals include symptom relief, improvement in psychological wellbeing, optimization of sexual function and quality of life, fertility assistance whenever desired, and a reduction in long-term health risks.

2. Hormone replacement therapy

Hormone replacement therapy is the most effective treatment for symptoms of hypoestrogenism. Moreover, there is fairly strong evidence to suggest that HRT use mitigates many of the long-term risks associated with a low-estrogen state.¹ Therefore, hypoestrogenism resulting from POI must be treated as other “endocrine deficiency states”, and physiological replacement with ovarian hormones (in doses higher than the ones used after natural menopause) is strongly recommended for reducing the long-term health risks associated with hypoestrogenism. The risks of hormone therapy use in women after natural menopause should not be extrapolated to these young women in whom lack of estrogen and other ovarian steroid hormones is pathologic. Unless contraindicated, HRT use is recommended until the average age of natural menopause (~51 years) even in women who do not have significant menopause related symptoms.^{1,20,37, 43–46}

While the benefit of HRT use is reasonably well established, the precise hormone regimens and long-term outcomes with their use have not been investigated in randomized control trials. The recommendations for treatment are based on expert opinion, and there are no consensus guidelines as such. In general, the goal of hormone therapy is to create a hormonal milieu that is comparable to that of a premenopausal woman with normal ovarian function. Hormone replacement therapy must be individualized based on age, patient characteristics and her preferences.^{20,37, 43}

In young women presenting with primary amenorrhea, the primary goal is induction of puberty with adequate breast and uterine development.⁴⁵ This is best achieved in close collaboration with a pediatric endocrinologist. An optimal approach is to use low dose estrogen initially, followed by progesterone for withdrawal bleeding several months later. A low dose combined oral contraceptive is best avoided because it does not provide the best results for puberty induction and uterine development.^{37, 46, 47}

Reproductive age women with POI should be treated with high doses of estrogen that result in hormone levels comparable to those in premenopausal women. This is achieved by using doses of estrogen about 2–3 times of those found in conventional hormone therapy regimens used after natural menopause. Some of the commonly used estrogen regimens are summarized in Table 2. However, even higher doses of estrogen are sometimes required in women who remain symptomatic despite using conventional estrogen replacement regimens, particularly with the transdermal route, which has the potential for suboptimal absorption. Concurrent progestogen use is recommended in women with an intact uterus for endometrial protection (Table 2).^{1, 20, 37,43,45, 48}

Table 2:

Hormone therapy regimens commonly recommended for use in premature ovarian insufficiency¹

Estrogens

Oral micronized 17β-estradiol: 2–3 mg/d Transdermal 17β-estradiol (patch, spray, gel): 100–150 mcg/d Vaginal ring 17β-estradiol: 0.1 mg/d

Progestogens 2

Oral micronized progesterone: ≥100 mg/d3 Oral medroxyprogesterone acetate:10–20 mg/d4 Levonorgestrel intrauterine system (intrauterine device): 52-mg device

¹This table is based on expert opinion. It provides the commonly recommended hormone replacement therapy regimens, but it does not provide all the available regimens and doses. It also does not provide the combined oral contraceptive regimens.

²There are no data regarding the optimal progestogen dosing for endometrial protection in the setting of high dose estrogen use in women with premature ovarian insufficiency. Higher doses are often required to prevent breakthrough bleeding.

³Continuous combined (100–200 mg/d) or sequential regimens (200 mg or higher, used for 12–14 days per month).

⁴Continuous combined regimen with 10 mg daily or sequential regimen with 20 mg for 12 to 14 days per month

Transdermal or oral 17β-estradiol use constitutes physiological estradiol replacement in comparison to conjugated equine estrogen. While the transdermal estradiol preparations may theoretically have a lower risk of cardiovascular disease and venous thromboembolism, the baseline risk for these conditions is low in these women due to their young age. As such, there are no clinical trial data comparing transdermal to oral estrogen formulations with respect to safety or efficacy in this patient population. Due to the higher doses of estrogen used in women with POI, the progestogen doses are also typically higher in these patients for providing adequate endometrial protection and for avoiding breakthrough bleeding. Oral micronized progesterone is commonly used in doses of 200 milligram or higher sequentially, for 10 to 14 days per month. Some patients may prefer to use a daily progestogen (continuous combined regimen) which typically avoids menstrual bleeding.

The use of combined oral contraceptives (COCs) may be considered more socially acceptable in this young patient population. However, even though randomized controlled trial data comparing COCs with HRT regimens are not available, the use of COCs is generally to be avoided for several reasons.²⁰ First, COCs contain much higher amounts of estrogen than the HRT formulations, therefore resulting in supraphysiologic dosing. Second, the risk for venous thromboembolism is higher with COC use. Finally, there is weak evidence to suggest less favorable effect on bone turnover markers with COC use.^49,50

Some women may experience genitourinary symptoms due to estrogen deficiency despite use of systemic estrogen therapy. Vaginal estrogen may be required in such patients, in addition to vaginal lubricants and moisturizers. The vaginal estrogen products and doses are similar to those recommended for women after natural menopause.

3. Androgen therapy and other aspects of management of sexual dysfunction

Androgen therapy is not routinely recommended to all women with POI. However, some women with POI, particularly those who undergo bilateral oophorectomy, and those with concurrent adrenal insufficiency may experience a substantial decline in androgen levels. Even though a consistent relationship between androgen levels and female sexual function has not been demonstrated, a fall in androgen levels can result in female sexual dysfunction. Women with POI due to bilateral oophorectomy may be candidates for testosterone supplementation if they have persistent sexual dysfunction despite adequate estrogen supplementation and management of genitourinary symptoms (Level 1, grade A recommendation).^31,51 Women with POI due to other causes have not been adequately studied in clinical trials to inform decision-making, but based on expert opinion, testosterone supplementation can be considered in them also for treatment of sexual dysfunction that persists despite use of optimal dose HRT.⁵¹ Testosterone supplementation in these patients should be guided by the global position consensus statement on the use of testosterone therapy for women, with regular monitoring of testosterone levels and a goal testosterone level in the premenopausal physiological range.⁵¹

Research data specifically in women with POI are sparse, but given the multidimensional etiology of sexual dysfunction in these women, it seems logical to use a multidisciplinary management approach. Moreover, a multidisciplinary approach has been shown to be beneficial in management of female sexual dysfunction after natural menopause. Extrapolating from those principles, in addition to HRT and androgen therapy when indicated, management of sexual dysfunction in women with POI should include psychological support and treatment of mood disorders, appropriate management of genitourinary symptoms arising from the estrogen deficiency, sex specific cognitive behavioral therapy whenever available, and pelvic floor physical therapy if needed.

Even though up to two-thirds of women with POI have may have sexual dysfunction,⁵² women often do not bring up sexual function-related concerns with their providers due to a variety of reasons. Yet, sexual dysfunction has a significant negative impact on the quality of life of these young women. Therefore, sexual function should be carefully and proactively assessed at the time of initial evaluation and during follow-up

4. Psychological support and management of mental health issues

The assessment and optimization of mental and psychosocial health must be an important component of management of women with POI. Their mental wellbeing and mood should be carefully and proactively assessed at the time of the initial evaluation and during follow-up.^1,20 Unfortunately, like many other health issues of women with POI, the evidence to guide management of mood disorders specifically in this patient population is sparse, and recommendations are based on expert opinion and extrapolation from the evidence in women after natural menopause. Experts stress the importance of a detailed and empathetic communication with the patient that facilitates shared decision-making. Patients should be provided with detailed education and information on POI. Given its anti-depressive and neuroprotective effect, estrogen therapy improves mood and mental wellbeing in most women. However, antidepressant therapy with or without psychotherapy may be required for women who continue to experience symptoms despite HRT use at recommended doses.

5. Fertility-related issues

Infertility or subfertility are the main features of POI and should be diligently addressed and managed as appropriate. It is important to make the distinction between women with established POI and those at risk for it. Appropriate counseling and referral to a reproductive endocrinologist should be considered as warranted by the clinical situation.

6. Managing long-term health risks

In view of the long-term cardiometabolic risk associated with POI, patients should receive counseling regarding lifestyle optimization with respect to eating a well-balanced diet, regular engagement in an aerobic exercise program, avoiding smoking, limiting salt and alcohol intake, and maintaining a normal body weight. Fasting glucose, hemoglobin A1C and lipid profile should be assessed at baseline, and annually thereafter if resources allow. Baseline and follow-up assessments of body weight, body mass index, and blood pressure should be part of standard care. Statin therapy should be considered as indicated, and referral to a specialist should be considered in women with high cardiovascular disease risk.^1,20

Given the association of POI with osteoporosis, a baseline bone density should be obtained in all patients. In women with normal bone density and adequate systemic estrogen use, repeated bone density assessment may have limited value. However, in those with a low bone mass at baseline, repeat bone density assessments can be made once every two to three years, or at more frequent intervals in women other risk factors for low bone mass. Referral to an endocrinologist should be considered in women with low trauma fractures or decline in bone density despite consistent and optimal HRT use.^1,20

The follow-up evaluations should also focus on ensuring adequate management of menopause symptoms, adherence with HRT use, optimization of mood, psychosocial well-being, and sexual function, with the overarching goal of providing these women their best chance at having a good quality of life.

UNMET NEEDS AND FUTURE DIRECTIONS

Hormone replacement therapy is underutilized in women with POI, mostly because of lack of knowledge regarding its pivotal role in preventing the long-term sequelae of premature menopause. Moreover, there are concerns and fears surrounding HRT use due to an inappropriate and unfair extrapolation of risks associated with hormone therapy use after natural menopause. There is an urgent need to educate the health care providers and patients on distinguishing POI from natural menopause and treating POI as an “endocrine deficiency state” requiring physiological hormone replacement.

It is surprising and concerning that despite the tremendous health impact of POI, there has been a negligible allocation of health care resources for understanding the consequences and appropriate management of this condition. There is a compelling need for directing global health care resources to facilitate our understanding of this public health issue with devastating consequences on the physical and emotional health of young women. Large scale, multinational randomized control trials and data registries are needed to establish consensus management guidelines.