Primary Ovarian Insufficiency

Etiology

Primary ovarian insufficiency is thought to arise from either follicular dysfunction or follicular depletion. However, the exact mechanisms in which POI develops remain unknown.[1][3] Approximately 90% of all diagnosed cases of spontaneous POI do not have a determined underlying etiology.[6] Starting at the level of the ovary, rare mutations in the genes for FSH and LH receptors can alter the ovaries’ response to these circulating gonadotropins leading to nonfunctional ovarian tissue.[1][2][7] Iatrogenic causes of POI such as oophorectomy, chemotherapy, or radiation, as well as women with mumps, varicella, malaria, shigella, and TB can destroy healthy ovarian tissue and substantially decrease the amount of functioning tissue that remains.[1][2][3][7] Chromosomal abnormalities such as Turner Syndrome (X,0) can lead to early oocyte apoptosis in utero, in addition to accelerated oocyte depletion early in life (before 10 years old). This leaves a woman with little to no ovarian reserve near reproductive age.[1] Fragile X FMR1 premutation (59-199 CGG trinucleotide repeats) significantly increases a woman’s risk of POI in comparison to the general population. Interestingly, women with FMR1 premutation of 80-100 CGG repeats are at the highest risk of POI.[1] Autoimmune diseases such as adrenal insufficiency (Addison disease), hypothyroidism (Hashimoto thyroiditis), rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, nontypical congenital adrenal hyperplasia, myasthenia gravis, and inflammatory bowel disease have also been associated with POI.[1][7] Genetic mutations and autosomal recessive diseases such as galactosemia (reduction of galactose-1-phosphate), ataxia-telangiectasia (ATM gene), and blepharophimosis-ptosis-epicanthus-inversus syndrome (known as BPES, a mutation in FOXL2) have undefined effects on POI.[1][2][7] Environmental exposures such as smoking, nicotine, and the various substances produced (dimethylbenzanthracene) are hypothesized to contribute to POI by binding to the receptors on ovarian granulosa cells. This leads to activation of proapoptotic genes and inhibits aromatase, ultimately leading to decreased circulating estradiol.[2] Other environmental exposures, such as substances in plastic production (phthalates, bisphenol-A), may contribute to POI, but the exact mechanism remains unknown.[7]

Epidemiology

The proportion of women that primary ovarian insufficiency (POI) impacts do not mirror the devastating effects that this disease spectrum causes. POI affects approximately 1 to 2% of women under the age of 40 and even fewer women under the age of 30 (approximately 0.1%).[5][6] This contrasts greatly with menopause, where the average age is 50 +/- 4 years.[3] Only 4% of women under the age of 45 years old will undergo menopause early.[3] The course of POI is variable and unpredictable. As such, approximately 4-10% of women with POI may conceive naturally and approximately 20% will have successful ovulation induction. However, due to the variability of the disease, the overall success of pregnancy and live birth only reaches 25% after cryopreservation and implantation of embryos. A women’s probability of pregnancy increases to approximately 40% in the setting of oocyte donation after one cycle of IVF and climbs to 70-80% with four cycles of IVF.[5] Within families who are affected by Fragile X Syndrome, 13-15% have the FMR1 premutation and POI. Overall, in women with no family history of Fragile X Syndrome, 2-5% will have the FMR1 premutation associated with POI.[7] In addition, therein lies a 24% chance that women will the FMR1 premutation (55-199 CGG repeats) will develop POI.[6] In regards to autoimmune disorders, thyroid autoimmunity in the absence of adrenal pathology is responsible for 14-27% of POI, insulin-dependent diabetes mellitus is seen in 2% of cases, and antibodies targeting acetylcholine receptors in myasthenia gravis is in 2% of cases.[2] In women who have adrenal autoimmunity, 20% have associated oophoritis. Of the patients diagnosed with Addison disease, 10-20% will also be diagnosed with POI.[2] In addition, 4% of women with POI will have 21-hydroxylase antibodies.[7] In children previously affected by malignancy and who have received chemotherapy/radiation, approximately 8% will develop POI by the age of 18. If radiation in combination with alkylating agents is used, then the risk of POI jumps to 30%. Lastly, 50% of women 21 years of age or older treated with similar alkylating agents will have POI.

Pathophysiology

Oocytes begin to develop in utero and reach their peak number (6-7 million) at 20 weeks gestation.[2] Oocytes are stored within microscopic primordial follicles just beneath the capsule of the ovary.[4] These oocytes arrest during the prophase of meiosis I.[8] At birth, women possess approximately 1-2 million oocytes, and by the time puberty is reached, only 300,000-400,000 oocytes remain.[2][4][8] Oocytes undergo constant attrition, and, as a result, only 400-500 oocytes are ovulated during a woman’s entire reproductive lifetime.[4] The process of ovulation begins with a surge of luteinizing hormone (LH), which triggers the maturation of the dominant Graafian follicle with the resumption of meiosis I. This dominant Graafian follicle is the primary source of estradiol in women of reproductive age.[4] Then, the cessation of maturation at metaphase II occurs until the oocyte is fertilized.[8] Overall, the pathophysiology of POI is not well understood as this disease is variable in nature. Ovulation, as outlined above, can occur randomly and unpredictably in POI patients. Dysfunction of the aforementioned process leads to anovulation, little to no production of estradiol, and the sequelae of a hypoestrogenic state.

History and Physical

To evaluate a patient for POI, it is important to obtain a thorough and complete history. Obtaining the history of present illness is critical as it may help to form the appropriate differential diagnosis. The history should include integral aspects such as age, medical comorbidities, gynecologic history, obstetric history, and social factors including potential stressors. When eliciting past medical history, it is very important to inquire about the history of various illnesses including but not limited to mumps, shigella, tuberculosis, malaria, and varicella. These diseases have the potential to affect the ovary causing oophoritis and potential damage to the oocyte reserve.[1] It is also imperative to discuss the possibility of any iatrogenic causes of POI to include oophorectomy, chemotherapy (alkylating agents/anthracyclines), or radiation.[7] Gynecologic history includes age at menarche, characteristics of the menstrual cycle, use of contraception, history of sexually transmitted diseases, and history of abnormal Papanicolaou smears. The characteristics of the menstrual cycle that should be obtained include occurrence, duration, the quantity of menstrual flow (light, moderate, or heavy), and any changes that the patient endorses. An obstetric history is to include a total number of pregnancies, which can then be further subdivided into term deliveries, preterm deliveries, abortions (either elective or spontaneous), and total living children. Obstetric history also includes natural versus medically assisted conception as well as the method of delivery, history of hemorrhage, and history of obstetric complications (gestational hypertension, gestational diabetes, preeclampsia with or without severe features, eclampsia, shoulder dystocia). Family history includes any inherited intellectual disability, tremors/ataxia, cognitive disease, birth defects, or autoimmune disorders. Social history including marital status, alcohol use, tobacco use, recreational drug use, and exercise frequency/intensity. In addition, a thorough review of systems can also aid in a more focused differential diagnosis based upon the signs and symptoms that the patient is endorsing. For example, in the setting of secondary amenorrhea, it is important to inquire about headaches, galactorrhea, or any changes in a patient’s visual fields as these are symptoms that may guide the physician towards further workup and evaluation of a prolactinoma.[9] A review of systems should also encompass endocrine abnormalities (heat intolerance, cold intolerance, fatigue, weight gain, weight loss, hot flashes, night sweats, palpitations, polyuria, polydipsia, diarrhea, constipation), genitourinary symptoms (dysuria, vaginal discharge, vaginal itching, vaginal dryness, or dyspareunia), and neurological symptoms (intellectual disability, visual field deficits, headaches, impaired memory).

The physical exam should include vital signs including blood pressure, heart rate, respiratory rate, and weight/body mass index. Then, a general survey of the patient should be performed looking for any pathognomonic signs of disease. For example, hirsutism, obesity, and acne may be indicative of PCOS or short stature, increased carrying angle, broad chest, and webbing of the neck may be indicative of Turner Syndrome.[3][10][11] The physical examination should also include palpation of the thyroid gland, which may indicate thyroid disease, and pelvic examination, which can help to identify any visible abnormalities of the genitourinary system.

Evaluation

While there is no consensus regarding criteria for evaluating POI, it is important to evaluate any female who presents with primary or secondary amenorrhea. POI is associated with various disease processes that may lead to either primary or secondary amenorrhea.[1] In patients with primary amenorrhea, evaluation should begin with karyotyping to evaluate for genetic abnormalities such as Turner syndrome.[1][4] It is important to obtain imaging of the patient’s reproductive tract, generally with the use of transvaginal ultrasound, in order to ascertain any obvious abnormalities, such as the absence of the uterus, fallopian tubes, or ovaries (e.g., Müllerian agenesis).[9] Pelvic ultrasound can provide information regarding the volume of the ovaries as well as antral follicle count within each ovary. In POI, ovarian volume is anticipated to be low with few to no antral follicles visualized.[7]

In the setting of secondary amenorrhea, first and foremost a pregnancy test must be completed to exclude pregnancy. Following a negative pregnancy test, it is appropriate to evaluate for any chronic medical conditions that affect the overall health of the patient (eg. uncontrolled diabetes, heart disease) as well as evaluation for any evidence of hypothalamic-pituitary axis depression in situations of extreme physical activity levels, depression, or anorexia.[3]

It would be appropriate to order various laboratory work such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and prolactin to aid in the evaluation and diagnosis of an endocrine abnormality.[9] If all laboratory work excluding FSH is within normal limits, POI can be diagnosed in the setting of 4-6 months of amenorrhea in association with two elevated menopausal range FSH values (> 40 IU/I) obtained 30 days apart.[1][3][5][9] Antimullerian hormone (AMH) can be obtained and is used as a marker for ovarian reserve, but is not part of the diagnostic criteria for POI.[7] Most women diagnosed with POI have AMH levels less than 1.[9] If on the physical exam there is evidence of hyperandrogenism, such as hirsutism, acne, clitoromegaly, or male pattern baldness, then it would be appropriate to evaluate the levels of 17-hydroxyprogesterone (21-hydroxylase antibodies), testosterone, and DHEA-S.[9] The aforementioned laboratory work would help to include or exclude the diagnosis of thyroid dysfunction (hypo- or hyperthyroidism) versus prolactinoma versus polycystic ovarian syndrome (PCOS) versus nontypical congenital adrenal hyperplasia that could be the cause of the patient’s secondary amenorrhea. Furthermore, autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, Hashimoto thyroiditis (thyroid peroxidase autoantibodies), and diabetes mellitus can be considered.[7]

If the etiology of POI remains undetermined after all of the aforementioned diseases have been appropriately excluded, then the next step in the evaluation of suspected POI would be to perform genetic screening. It is possible to use a patient’s family history to guide the physician in ordering the correct genetic screening test. However, it is important to remember that the impact of these associated gene mutations on POI has not been robustly determined.[1][4]

Treatment / Management

Treatment of POI is largely based on estrogen repletion to diminish vasomotor symptoms, maintain bone density, decrease fracture risk, decrease cardiovascular and autoimmune morbidity and mortality, protect cognitive function, and improve the overall well-being of the patients affected.[6][7] The objective of treatment is to ensure that women diagnosed with POI maintain a daily level of 100 pg/mL of estradiol, as do premenopausal women with normal ovarian function. The mainstay of treatment of POI remains estradiol (17B-E2) replacement via transvaginal application or transdermal patches, as both these routes decrease the overall risk of venous thromboembolism (VTE) as compared to oral estrogen replacement.[6][7] A vaginal ring or patch delivers 0.100 milligrams of estradiol daily, allowing for the aforementioned estradiol goal to be achieved.[6] This should be continued until the average age of menopause (50.5 years old in the United States). In premenopausal women, it is imperative to include progesterone supplementation for the prevention of endometrial hyperplasia and the possibility of progression to endometrial carcinoma. Oral progesterone or transdermal progesterone may be utilized (see table below).[7]

Of note, in premenopausal women with POI who desire fertility, cyclic bleeding cycles are preferred to maximize their chances of successful embryo transfer or even naturally occurring pregnancy.[7] In premenopausal women, it is also possible to begin oral contraceptives (OCP). This modality of treatment also incurs a higher risk of venous thromboembolism and does not provide adequate daily physiologic repletion. Typical use of OCPs (1 week of placebo/month) sums up to 12 weeks of estrogen deficiency that may result in symptoms associated with a hypoestrogenic state as discussed elsewhere. In women with POI who are status post hysterectomy, it is appropriate to utilize estrogen therapy alone. In women with vaginal atrophy, dyspareunia, or vaginal dryness/itching/irritation, topical estrogen creams may be applied for symptomatic relief or improvement.[5][7] 

In regards to assisted reproduction and fertility, there is no evidence that ovulation induction can be reliably achieved with gonadotropins or GnRH analogs. Spontaneous ovulation in women with POI has shown the greatest success of pregnancy.[7] It is possible in the future that the etiology of POI can be further defined and additional treatment regimens may be determined to enhance fertility. For example, in one study, daily DHEA and melatonin supplementation in combination with HRT showed a slight increase in successful pregnancy rates as compared to women on HRT therapy alone.[12] Experimental studies on mice models have attempted ovarian grafts and bone marrow transplants (germline stem cells) to generate functioning oocytes. Both of these methods remain controversial and clinically inapplicable to the human population.[2] Ultimately, oocyte donation in women with POI remains the highest probability of achieving pregnancy. (B2)

Furthermore, diagnosis of POI can incur devastating psychological effects not only for the patient but also for the patients’ significant other and family. It is imperative that the patient is followed closely in the clinic and given the resources necessary to establish care with a behavioral health specialist and therapist to facilitate discussion and coping with the emotional stressors associated with POI.[3]

Differential Diagnosis

Differential diagnosis may include any of the aforementioned disease processes. However, the presence of POI within each disease is not absolute. In patients with primary amenorrhea, it is necessary to differentiate between chromosomal abnormalities (e.g., Turner syndrome) or Mullerian anomalies (e.g., Mullerian agenesis, imperforate hymen). In women with secondary amenorrhea, it is imperative for pregnancy to be ruled out as the underlying etiology. Nutritional status and activity level must be evaluated to exclude the possibility of functional hypothalamic dysfunction causing menstrual irregularity. Endocrine abnormalities such as hyper- or hypothyroidism, prolactinoma, diabetes mellitus, and congenital adrenal hyperplasia may be the underlying mechanism of infertility rather than POI. Autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, or Addison disease can be present without evidence of POI. The polycystic ovarian syndrome may be the etiology of menstrual irregularity and anovulation leading to infertility. Early menopause may be considered in a small subset of the female population greater than 40 years of age but less than 45 years of age.

Prognosis

The diagnosis of primary ovarian insufficiency should be based upon strong evidence after any confounding disease processes have been excluded. This diagnosis carries with it severe implications on a women’s future health, fertility, and psychological well-being, as discussed above. Currently, there are no treatment modalities that can reverse the damage done to healthy oocytes, increase the functionality of existing oocytes, or even generate new oocytes. Spontaneous pregnancy may be achieved as the course of POI is unpredictable. However, this chance remains low. If a woman with POI desires fertility, the mainstay of successful treatment remains oocyte donation.

Complications

Symptoms of POI such as hot flashes, mood irritability, night sweats, sleep disturbance, vaginal dryness/irritation, and dyspareunia can be a nuisance for women. However, they are not life-threatening and can be improved by hormone replacement.[6] Hormone replacement incurs potential complications that can be devastating, including increased incidence of deep venous thrombosis, pulmonary embolism, and cerebrovascular accidents.[3] Other long-term complications stemming from POI include decreased global cognitive function and decreased bone mineral density leading to osteoporosis, osteopenia, and increased fracture risk.[1][5] Overall, the greatest health impact of POI affects a woman’s cardiovascular health, leading to early mortality from ischemic heart disease.[5] As previously discussed, infertility from POI can cause lasting psychosocial effects (anxiety, depression, sexual disorders) and impair overall well-being.[4][5]