Group III ovulatory disorders is defined as ovarian insufficiency or failure with a hypergonadotrophic-hypogonadic profile that affects 5% of women with ovulatory dysfunction [22
]. Women possess a finite number of oocytes that gradually declines resulting in critically low levels in the mid to late 40’s leading to clinical menopause by early 50’s. Early depletion of ovarian function before the age of 40, associated with elevated FSH or low estradiol levels, is defined as premature ovarian insufficiency (POI), formerly known as premature ovarian failure. Multiple known etiologies of POI exist, including genetic, acquired or iatrogenic causes with the majority remaining idiopathic. Supplementary Materials Table S1
outlines all ovulation disorders, summarizing the various etiologies.
4.1. Genetic Causes
Despite a low incidence, the most common genetic form of POI remains Turner syndrome, 45 XO, with either complete or partial X chromosome deletions. These patients commonly present with primary amenorrhea due to accelerated oocyte depletion.
The second most common cause of POI is chromosomal aberrations. Approximately 10–30% of cases appear to be familial, primarily exhibiting an x-linked inheritance pattern with varying penetrance [23
]. Several specific gene mutations have been proven to correlate with POI. Well described is the fragile X gene premutation (FMR1) associated with CGG triple nucleotide repeat expansions (55–200) leading to POI [25
]. FMR1 is an RNA-binding protein that has suppressive effects on gene expression whereby increased CGG repeats leads to overexpression of FMR1, which downregulates oocyte development genes, causing premature follicle atresia. CGG repeats greater than 200, considered a full FMR1 mutation results in complete loss of protein function, sparing ovarian function, though causing as intellectual disability in males. FMR1 premutation expansion can occur, causing maternal transmission of a full mutation to offspring.
Additional candidate genes have been proposed to be causative, however lack sufficient evidence. New headways illustrating causes for POI includes mutations in transcription factors such as nuclear receptor subfamily five group A member 1 (NR5A1), newborn ovary homeobox (NOBOX
) and factor in germline alpha (FIGLA
) that are responsible for gonadal differentiation and folliculogenesis [26
]. Furthermore, recent studies are shedding light on the possibility of steroid receptor and folliculogenesis growth factor mutations. Recently, copy number variants (CNVs) and microRNAs have been explored for their involvement in POI. Although additional studies are required to validate these findings, much progress is being made in identifying precise etiologies.
4.2. Acquired Causes
Autoimmune thyroiditis leading to hypothyroidism is the most common autoimmune disorder associated with POF. Additionally, anti-ovarian antibodies have been demonstrated targeting steroid producing cells and gonadotropin receptors. Furthermore, there are two types of autoimmune polyglandular syndromes (APS), type I and II, associated with endocrine gland and extra-glandular tissue destruction reported to cause POI. APS type I affects younger children, with 60% of girls affected experiencing primary amenorrhea and POI. Type II causes gonadal failure in 4% of affected individuals [27
]. Associated autoimmune disorders linked to APS include Addison’s disease (autoimmune adrenal insufficiency) and less commonly type 1 Diabetes Mellitus, and Celiac disease [28
]. The autoimmune process involves a genetic predisposition with environmental factors leading to the accumulation of dendritic cells and superabundance of lymphocytes causing tissue damage [29
Common gynecologic disorders may also contribute to accelerated reproductive aging. Endometriosis affects 10% of reproductive aged women. In addition to structural pathologies, ovarian endometriosis may lead to ovarian destruction and consequently a hypoestrogenic state. A study performed by Cahill et al. described endometriosis related diminished LH levels in serum and follicular fluid impacting ovulation [30
]. Inevitably, monthly fecundity decreases from 15–20% to 2–10% in a normal healthy woman affected by even mild stages of endometriosis.
A number of environmental toxins may lead to POI. Effects of cigarette smoking have been extensively investigated. Smoking is associated with accelerated follicular atresia, displayed by significant lower AMH and earlier onset of menopause [31
]. Environmental exposures also linked to ovarian failure, although still controversial and lacking powered studies, include infections such as CMV, mumps, and tuberculosis. Tuberculosis, although uncommon in developed countries, is responsible for a considerable rate of infertility cases in developing countries accounting for 5–10% of subfertility worldwide [32
]. Most notably, if ovarian tuberculosis transpires (described as latent genital tuberculosis), diminished ovarian reserve and even ovarian insufficiency may ensue [33
4.3. Iatrogenic Causes
As oncologic treatments continue to improve, and the number of cancer survivors continue to increase, so does the rate of iatrogenic ovarian insufficiency. Cancer therapy causes oocyte depletion in several ways, the most common being inhibiting growth and proliferation of cells that support oocytes. How chemotherapeutic drugs affect immature oocytes is still unclear, however commonly used toxins including alkylating agents, work by interlinking DNA causing breaks that damage the cell [34
]. Additionally, anthracyclines, platinum agents as well as treatment regimens that include procarbazine [35
], exhibit high rates of ovarian failure [36
]. As most cancer treatment are multidrug protocols, newer studies are focused on effects of various regimens on gonadal function. Dose related effect on ovarian reserve is being further investigated.
Pelvic and total body irradiation has significant ramifications on ovarian function. Radiation doses as low as 4–5 Gy results in permanent loss of ovarian function. Knowing these treatment modalities confer poor prognosis for post-therapy gonadal and uterine function, careful consideration can be made in planning for future fertility. The field of onco-fertility is ever growing, with fertility preservation becoming increasingly available.
4.5. Evaluation and Management of Ovarian Insufficiency
Ovarian insufficiency can be diagnosed by measuring AMH, estradiol, FSH levels and antral follicle count. Though spontaneous pregnancy is not impossible, it is certainly much more difficult to achieve without intervention. Patients faced with such a diagnosis should be provided reassurance and guidance to the alternate reproductive options currently available.
Evaluation approach is dependent on medical history and physical examination. Reproductive aged women less than 35 years old with rapidly declining ovarian reserve warrant genetic and infectious disease testing. If genetic testing is abnormal, genetic counseling is prudent.
Patients with Turner syndrome may present with lack of pubertal milestone or primary amenorrhea. Mosaic Turner syndrome patients may be aware of their diagnosis prior to complete follicular atresia and can salvage their fertility by means of oocyte and/or embryo cryopreservation. With newer vitrification techniques, oocyte cryopreservation has become a reliable and available method for fertility preservation [37
]. In fact, immature eggs can be matured in vitro and subsequently frozen for future use. Frozen oocytes have comparable fertilization rates to fresh oocytes [38
]. These patients may benefit from preimplantation genetic testing for euploid embryo transfer to optimize pregnancy outcomes.
Onco-fertility patients also greatly benefit from oocyte or embryo preservation prior to gonadotoxic therapy. In recent years, random start ovarian hyperstimulation in preparation for egg retrieval allows physicians to shorten treatment duration to proceed with chemoradiotherapy [39
]. In a specific category of breast cancer patients, letrozole is co-administered with gonadotropins for a theoretical concern over elevated estradiol level stimulating estrogen receptor positive tumors [40
]. Additionally, ovarian tissue cryopreservation may be offered to cancer patients who are prepubertal or cannot undergo ovarian stimulation with egg harvesting and freezing. Frozen ovarian tissue may be thawed followed by auto-transplanted upon completion or treated with in vitro maturation of oocytes. Previous studies have confirmed return of ovarian function and live births after transplanting the cryopreserved tissue [41
]. If women requiring chemotherapy wish to omit cryopreservation, gonadotropin releasing hormone agonists (GnRHa) have shown some efficacy in preventing treatment induced POI [43
IVF with donor oocytes currently remains the most successful treatment modality for women with POI or age related diminished ovarian reserve. Currently available options of fresh or frozen or known vs. unknown donors provides patients with more options. Furthermore, women may opt to have their young relatives, with abundant ovarian reserve, to donate oocytes to them [44
The use of mesenchymal stem cells (MSCs) has been emerging as a treatment option for patients with POI. Stem cell therapy has particularly been studied in the setting of iatrogenic ovarian destruction and shown great promise. Various sources of stem cells under investigation for this purpose include umbilical cord MSCs (UCMSCs), induced pluripotent adult stem cells (iPSCs), and embryonic stem cells. Mouse models with chemotherapy induced ovarian insufficiency undergoing subsequent treatment with UCMSCs have demonstrated improved ovarian function with recovery of sex steroid levels and decreased cumulus cell apoptosis [45
]. The suggested mechanism of ovarian rescue is explained by prevention of granulosa cell apoptosis. This maintains FSH receptor (FSHR) expressivity, and in turn prevents overproduction of FSH. As FSH exceeds a normal range secondary to low FSHR activity, accelerated follicular depletion is observed [47
]. Additional studies have demonstrated administration of bone marrow MSCs restoring ovarian function in a similar manner.
More novel therapeutic options are beginning to make strides for age related oocyte quality improvement. One suggested mechanism responsible for depleted ovarian reserve involves mitochondrial dysfunction [48
]. Though still early in its experimental stage, autologous germline mitochondrial energy transfer (AUGMENT) has been performed with live births reported [49
]. The utility of AUGMENT has limitations in patients with POI due to the need for abundant mature oocytes.
Those affected by POI have health implications if they remain in a chronic hypoestrogenic state including as cardiovascular risk, sexual function and bone health. Hormone replacement therapy (HRT) should be encouraged through use of estrogen therapy with cyclic progestin if a woman still has her uterus. Those who no longer have a uterus, estrogen replacement alone is recommended. HRT is important to reduce the risk of morbidity and mortality as it mimics normal ovarian function until the natural age of menopause [50
]. Dose titration and discontinuation of HRT should be considered at the average age of menopause, approximately 50 years of age.