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Primary Ovarian Insufficiency

Current State of Understanding

Clinical Summary

Pathophysiology

Therapeutic Targets

Companies of Interest

Summary

Appendix

1. Current State of Understanding:

Definition & Epidemiology

Primary ovarian insufficiency (POI) is a term used to describe impaired ovarian function on a continuum, rather than a specific endpoint.

POI can be transient or progressive and usually results in eventual premature menopause.

POI affects one in 10,000 women by the age of 20 years and one in 100 by the age of 40 years.

POI is characterized by one of two processes: ovarian follicular dysfunction or depletion of functional primordial follicles before the age of 40 years.

Lifelong Morbidity

Long-term consequences of hypoestrogenism include osteoporosis, accelerated cardiovascular aging, and neurocognitive disorders.

Infertility is another consequence of POI.

Risk Factors

The cause of POI is largely unexplained, but potential etiologies can be divided into genetic, autoimmune, metabolic dysfunction, infectious, environmental and iatrogenic categories.

Genetic Factors

Pathophysiology

Three potential mechanisms can be associated with POI: a congenital decrease in primordial follicles, accelerated follicular atresia, and an inability to recruit primordial follicles.

Future Direction

DEFINITIONS AND EPIDEMIOLOGY

The age-specific incidence of POI is approximately 1 in 250 by age 35 years and 1 in 100 by age 40 years.

Menopause before age 40 years is considered to be abnormal and is referred to as primary ovarian insufficiency (POI).

The terms "premature menopause" and "premature ovarian failure" are inaccurate because many patients with POI intermittently produce estrogen and ovulate, a few experience intermittent return of regular menses, and women can conceive and have a normal pregnancy even many years after the diagnosis.

POI is a spectrum disorder and is a continuum of impaired ovarian function.

Diminished ovarian reserve is not synonymous with POI. It is a term used in the context of female infertility evaluation and treatment.

Clinical Summary

Symptoms

Primary ovarian insufficiency (POI) affects 1% of women before 40 years of age and is associated with significant morbidity and mortality.

POI can manifest as pubertal delay and primary amenorrhea (PA), secondary amenorrhea (SA), or oligomenorrhea of less than 4 months.

Patients typically present with oligomenorrhea or amenorrhea and may exhibit increasing symptoms of estrogen deficiency.

About 50% of patients will have varying degrees of residual ovarian function, and it is estimated that approximately 5%–10% are able to conceive spontaneously.

POI is a spectrum disorder with a change in menstrual function, elevated serum gonadotropins, and low serum estradiol concentrations

Vasomotor symptoms may begin before the development of abnormal menstrual cycles and dyspareunia eventually become prominent in the absence of estrogen replacement

POI is associated with increased risk of bone loss and osteoporosis, cardiovascular morbidity and mortality, diminished sexual well-being, and emotional disorders

Women with POI may develop related depression and anxiety disorders

Evaluation

Lack of consensus on evaluation criteria

most women with POI have no abnormalities on physical examination, but occasionally, physical features such as ovarian enlargement or evidence of autoimmune disorders may be present

Evaluation Process for Primary Amenorrhea

Initial evaluation with karyotyping for genetic abnormalities, e.g., Turner syndrome

Imaging of the patient's reproductive tract, usually using transvaginal ultrasound

to find any obvious abnormalities, like absence of uterus, fallopian tubes, or ovaries

Use of pelvic ultrasound

To gather information about ovarian volume and antral follicle count

Low ovarian volume and few to no antral follicles expected in POI

Evaluation Process for Secondary Amenorrhea

Pregnancy test to exclude pregnancy

Assessment of chronic medical conditions that affect patient's health, e.g., uncontrolled diabetes, heart disease

Evaluation for hypothalamic-pituitary axis depression in cases of extreme physical activity, depression, or anorexia

Diagnosis

Diagnostic criteria for POI if all lab work, except FSH, is normal: The diagnosis of POI should be confirmed by obtaining two follicle-stimulating hormone (FSH) levels in the menopausal range (.30 U/L) at least 1 month apart in the setting of 4–6 months of amenorrhea.

Biochemical features of POI include low serum estradiol and elevated serum FSH concentrations, and antral follicles can be detected by transvaginal ultrasound examination in nearly 75 percent of women with 46,XX POI

The ovarian reserve (OR) can be evaluated by transvaginal ovarian ultrasound (US) with antral follicular count and/or by anti- Müllerian hormone (AMH) determination.

Low/undetectable AMH indicates a dramatic diminution of the OR, predicting poor success of fertility preservation.

Women who have intermittent ovarian function may have normal laboratory findings despite having ovulatory menstrual cycles

Order of lab work such as FSH, LH, TSH, and prolactin to identify any endocrine abnormality

If physical exam shows hyperandrogenism, levels of 17-hydroxyprogesterone, testosterone, and DHEA-S should be evaluated

Excluding Other Conditions

Lab work helps to confirm or rule out other conditions like thyroid dysfunction, prolactinoma, PCOS, nontypical congenital adrenal hyperplasia

Consideration of autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, Hashimoto thyroiditis, and diabetes mellitus

Genetic Screening

If the cause of POI remains undetermined, the next step is genetic screening

A patient's family history can guide the physician in ordering the appropriate genetic screening test

The impact of associated gene mutations on POI has not been robustly determined

Management

Many clinicians are unaware of the advantages of early POI diagnosis and fail to provide integrated personal care to address all the clinical needs.

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PATHOGENESIS

Normal ovarian development is dependent on a carefully timed cascade of events; as a result, there are multiple potential etiologies for ovarian dysfunction. Pathophysiologically, these defects can be divided into two major categories:

Accelerated follicle depletion Decreased steroid production without oocyte loss

Other theoretical causes of ovarian failure, including absent germ cell migration or defective ovarian development, have not yet been described, although some genes appear to play a role in normal ovarian development.

Pathophysiology

Three potential mechanisms can be associated with POI: a congenital decrease in primordial follicles, accelerated follicular atresia, and an inability to recruit primordial follicles.

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I. Pathophysiology of Premature Ovarian Insufficiency (POI) A. Ovary as the primary female reproductive organ 1. Performs gametogenic and secretory functions 2. Necessary for the production of sex hormones 3. Helps regulate hormonal growth, reproductive cycle, and menstruation

B. Ovarian Dysregulation 1. Impact on a woman’s physiological or reproductive functions

C. Components of Follicles 1. Granulosa cells (GCs) and oocytes are essential for ovarian functioning 2. GCs control oocyte growth and maintain follicular evolution through the secretion of growth factors and hormones 3. The expression of hormone receptors in GCs, e.g., follicle-stimulating hormone receptors (FSHR), is critical for ovulation and folliculogenesis

D. Number of Operational Oocytes 1. Indicates a female's reproductive capacity 2. Mature oocytes and GCs interact with growth hormones/factors like bone morphogenetic proteins (BMPs) and FSH during folliculogenesis

E. Causes of POI 1. Causes often unknown but expedited GCs and oocyte apoptosis obstruct follicle maturation 2. Anomalies in follicle activation are key mechanisms of POI 3. Hypothalamic–pituitary–ovarian axis regulates ovarian function

F. Regulation of Folliculogenesis 1. Primary hormones that regulate folliculogenesis are FSH and LH 2. GCs secrete anti-Müllerian hormone (AMH) during primordial follicle and initial antral follicle phases 3. AMH plus estrogen negatively affects follicular growth and influences FSH levels

G. Disruption of Granulosa Cells 1. Chemotherapy or other treatments disrupt GCs, causing decreased estrogen and AMH levels 2. This leads to an increase in FSH and depletion of the follicular pool

H. Detection of POI 1. Indicated by decreased estrogen and AMH secretion and increased FSH secretion 2. Understanding these mechanisms aids in the development of effective treatments for ovarian dysfunction

I. Folliculogenesis in POF 1. Normal and pathological symptoms are depicted in Figure 1.

Risk Factors

Genetic causes of POI

A great leap in the genetics of POI was achieved by the major methodological progress of next generation sequencing (NGS) and in particular whole exome sequencing (WES).

more than 60 genes have been identified and has enabled genetic diagnosis by NGS

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link to this figure

Other Causes

3. Racial differences in ovarian reserve

· Recent evidence suggests that ovarian reserve varies among racial/ethnic groups

· Seifer et al provided evidence of racial differences in ovarian reserve measured by AMH

· The study compared AMH levels in a racially diverse cohort of HIV-infected women

· Black women had average AMH levels approximately 25.2% lower than whites after controlling for various factors

· Hispanic women had AMH levels 24.6% lower than white women, although this difference was not statistically significant

4. Diagnosis and evaluation

· POI does not have specific biomarkers or signs/symptoms to predict when menopause will occur

· Patients may present with a shortening or increase in the intermenstrual cycle interval, menstrual irregularities including oligomenorrhea, dysfunctional uterine bleeding, or amenorrhea

· Women may note symptoms of estrogen deficiency such as vasomotor symptoms, mood disturbances, and atrophic vaginitis

· Long-term consequences of hypoestrogenism include osteoporosis, accelerated cardiovascular aging, and neurocognitive disorders

· Standardized diagnostic criteria for POI have yet to be established

· The screening history should focus on family history, previous ovarian/pelvic surgery, chemotherapy or radiation therapy, autoimmune disorders, fragile X syndrome, or intellectual disability

· Laboratory testing should include human chorionic gonadotropin, FSH, thyroid-stimulating hormone, prolactin, and estradiol levels

· Other diagnostic tests include transvaginal ultrasound imaging of the ovaries and cycle day 3 FSH levels, AMH, inhibin B, and transvaginal ultrasound-determined antral follicle count to assess ovarian reserve

· Elevated FSH levels drawn on day 3 imply a poor ovarian reserve

· Women with POI may experience loss of bone mass and not achieve peak bone density due to decreased estrogen levels

· Hormone therapy may be effective in treating hypoestrogenic symptoms

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to elucidate the etiology and identify covert comorbidities (Table 2)

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Diagnostic insights related to the genetic underpinnings of POI

Certain karyotypic abnormalities and single-gene mutations have long been recognized as causes of POI (Table 3).

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Advances of therapeutic relevance for POI-associated infertility: toward a plausible “cure”?

- The mechanism behind why some primordial follicles remain dormant while others activate for growth is poorly understood.

- Stem cell therapy, particularly bone marrow-derived stem cells (BMDSCs) and endometrial mesenchymal stem cells (MSCs), have shown promise in restoring ovarian function and fertility.

- Intra-ovarian injection of platelet-rich plasma (PRP) has been shown to support preantral follicles' growth and increase the number of retrieved oocytes.

- Ovarian tissue cryopreservation (OTC) is a promising preventative option for fertility preservation in women planning initiation of chemotherapy or radiation, particularly those with cancer diagnosed before puberty.

- Investigation into the gene expression pathways regulating primordial follicle growth activation and recruitment, including the c-Kit/Kit ligand signaling pathway, FOXO3, and members of the PTEN pathway, is a promising area of study as a therapeutic target.

- In vitro activation, buoyed by recent advances in understanding the Hippo signaling pathway's role in activation of residual dormant follicles, has been proposed as a novel strategy for reactivating the dormant primordial follicle.

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Figure 2. Selected pathways relevant for plausible salvaging of residual ovarian function in primary ovarian insufficiency. (1) Ovarian cortex fragmentation disrupts the Hippo signaling pathway leading to dephosphorylation of YAP and TAZ, which (2) stimulates transcription of growth factors (GFs), including GDF9 and BMP15 (transforming growth factor-beta family). (3) GF and Kit-ligand (Kit-L) as well as (4) 740YP administration increase PI3K activity, whereas PTEN serves to keep follicles dormant. (5) Activation of the PI3K complex activates PIP2 to PIP3, which (6) leads to increased Akt expression. (7) Phosphorylated Akt upregulates mTOR, leading to downstream GF transcription, and (8) inhibits activation of RAD51 and FOXO3A. (9) This prevents nuclear export of FOXO3A, decreasing primordial follicle activation. Similarly, (10) anti-Müllerian hormone (AMH) decreases activation of phosphorylation of FOXO3A. Green arrows represent activation steps, and red bar-headed lines represent inhibition. AKT, protein kinase B; FOXO3, forkhead box O3; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-bisphosphate; PMF, primordial follicle; PTEN, phosphatase and tensin homolog deleted on chromosome 10; TAZ, transcriptional coactivator with PDZ-binding motif; YAP, Yes-associated protein.

Innovative Treatments for POI

Embryo transfer from donated oocytes is the most frequent therapeutic approach for infertility in POI patients.

Fertility preservation through tissue cryopreservation before chemotherapy is an important method for preventing POI.

Cryopreservation of ovarian tissue as fertility preservation should be carried out as soon as the risk of follicular decrease has been identified.

Human ovarian follicles can be activated when ovarian tissue is cut into small pieces and placed in organ culture, and Hippo signaling was identified as the regulatory factor in this activation.

Full oocyte maturation can be achieved after stimulation of residual follicles in ovarian tissue from POI patients by cutting the tissue into small pieces, and subsequently exposed to PTEN inhibitors and Akt activators prior to transplantation.

Recent technological developments with induced pluripotent stem cells allow the reconstitution of complete oogenesis, and tissue engineering to generate ovarian implants are promising leads that may help restore fertility.

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Figure 5. Flow Chart for Primary Ovarian Insufficiency Diagnosis and Treatment. After the initial diagnosis of primary ovarian insufficiency (POI), family investigation and evaluation of the follicular reserve by anti-Müllerian hormone (AMH) assay and antral follicular count (AFC) are performed. Specific causes are eliminated. In the case of unexplained POI, karyotype and FMR1 study are performed. In all cases hormonal treatment has to be started. In isolated POI, array comparative genomic hybridization (aCGH) or next generation sequencing (NGS) can highlight defects in genes involved in ovarian differentiation or in the establishment of the follicular pool. This, together with the undetectable ovarian reserve, will lead to genetic counseling in the patient and relatives and therapeutic counseling for the patient’s infertility by a multidisciplinary team. If there is a wish to conceive, egg donation will be performed. In the case of a detectable ovarian reserve and/or a defect in genes involved in follicular maturation, genetic counselling will be performed in the patient and relatives and therapeutic counseling will lead to fertility preservation. In the future, in vitro activation (IVA) of small follicles might be performed. In syndromic POI, NGS of specific genes will be performed according to the clinical phenotype of the patient. Specific treatment of associated symptoms is needed. AFC antral follicle count; DSD, disorder of sexual differentiation; FSH, follicle-stimulating hormone; PA, primary amenorrhea; PRL, prolactin; PTH, parathyroid hormone; SA, secondary amenorrhea; TSH, thyroid-stimulating hormone; US,ultrasonography; VWM, vanishing white matter.

Innovative therapeutic options for POI

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Mitochondrial activation technique

- Mitochondria are power sources of cells that produce ATP and regulate various pathways such as calcium signaling, redox potential, and apoptosis.

- Mitochondrial dysfunction is one of the causes of ovarian aging and includes mtDNA dysfunction, oxidative damage, altered membrane potential, and inefficient biogenesis.

- Excessive accumulation of ROS in POI populations drives mtDNA mutations and energy deficiency, leading to aging and apoptosis.

- Disturbances in mitochondrial dynamics also affect oocyte aging, and key proteins such as MFN2 and Drp1 are crucial for maintaining oocyte quality.

- Pharmacological methods such as CoQ10, resveratrol, and melatonin have been found to restore mitochondrial vitality and delay ovarian aging.

- Various mitochondrial transfer therapies have been tested for infertility management, including allogeneic ooplasmic transfer, spindle transfer, GV transfer, PNT, and AUGMENT.

- However, these techniques are limited by ethical concerns and potential transmission of mitochondrial diseases or heteroplasmy. Current research on these procedures is still preliminary, and it is too early to apply them to clinical practice.

Stem cell therapy

- Stem cell therapy is being explored as a way to restore ovarian function and fertility in patients with primary ovarian insufficiency (POI).

- Stem cells have the ability to self-renew, proliferate, and differentiate into various cell types, and can be classified as embryonic, adult, or induced pluripotent stem cells.

- Stem cell therapy exerts its therapeutic effect through homing, differentiation, and paracrine signaling, which involves the secretion of various biologically active molecules that influence adjacent cells and improve ovarian function.

- Stem cells also secrete exosomes, which are extracellular vesicles that mediate cell-to-cell communication and can initiate repair and regeneration processes.

- Stem cell-mediated mitochondrial transfer is a novel mechanism that involves the transfer of mitochondria from stem cells to adjacent cells through tunnel nanotubes, and may rescue oocyte quality and embryo development.

- Embryonic stem cells raise ethical issues, but induced pluripotent stem cells can be used without ethical concerns and have been shown to differentiate into oogonia/gonocyte-like cells.

- Mesenchymal stem cells (MSCs) have been studied extensively for the treatment of POI and have been shown to increase estrogen levels, restore follicle numbers, and inhibit ovarian fibrosis and apoptosis.

- Various types of MSCs have been used, including bone marrow, adipose-derived, menstrual blood-derived, placenta-derived, umbilical cord, and amniotic fluid stem cells.

- MSC therapy can improve POI through various mechanisms, such as inducing angiogenesis, reducing apoptosis, upregulating antioxidant factors, and regulating signaling pathways.

Cell‐free therapy for POI

- Exosomes derived from stem cells can be used for cell-free therapy for POI and have higher clinical safety due to lower risk of immune rejection, vascular obstruction, and tumor mutation.

- Exosomes and their derived miRNAs from various stem cell sources have been shown to alleviate POI by targeting apoptosis, regulating pathways such as SMAD, SIRT7, and FOXO, and inhibiting follicular atresia.

- Biomaterials such as collagen, alginate, and hyaluronic acid can be used for stem cell transplantation to enhance retention, drug delivery, and culture of follicles.

- Safety measures such as ensuring directional differentiation, purification, and careful selection of cell lines are necessary to avoid tumorigenicity and immunogenicity.

- MSCs with low immunogenicity and tumorigenicity are considered safe sources of stem cells for POI treatment, but the therapeutic effects may be affected by various factors such as the quality and quantity of cell products amplified in vitro, route of injection, optimal dose, and timing of treatment.

PRP intra‐ovarian infusion

- PRP (platelet-rich plasma) is a novel approach to treating POI (primary ovarian insufficiency) by intra-ovarian infusion.

- PRP is composed of high concentrations of platelets, which contain hormones, growth factors, and other bioactive proteins that promote cell proliferation, differentiation, angiogenesis, and tissue regeneration.

- The mechanisms underlying the role of PRP in the treatment of POI remain unclear, but some studies have reported that PRP promotes the development of follicles and restores the ovarian microenvironment, preventing oxidative stress and reducing degeneration and atresia of follicles.

- Clinical application of PRP in human ovaries has shown positive results in restoring ovarian functionality and hormonal profile, increasing ovarian vascularization, and improving IVF outcomes.

- Advantages of autologous PRP intra-ovarian infusion include easy handling, good storage properties, and low immunogenicity, but potential risks include infection, intense cell proliferation events, and unknown detrimental effects on the embryo.

- Further studies are needed to confirm the safety and efficacy of PRP therapy for POI.

MicroRNAs: the future direction of POI treatment

miRNAs are non-coding RNAs that regulate cell proliferation, differentiation, and apoptosis.

miRNAs are potential biomarkers for diseases, including POI.

A miRNA microarray analysis identified several critical miRNAs in POI, including miR-23a, miR-27a, and miR-127-5p.

MiR-23a and miR-27a induce GC apoptosis and reduce oocyte maturation, while miR-127-5p inhibits the proliferation of GCs and impairs DNA damage repair.

A study found that miRNA-146b-5p overexpression attenuates POI in mice by downregulating p38-Mapk14 and inhibiting γH2A.X phosphorylation.

PLGA nanoparticles were used as a carrier to deliver miRNA-146b-5p to GCs derived from a mouse POI model, resulting in downregulated p38-Mapk14 and alleviated aging.

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