Wrodzona niewydolność jajników – Patofizjologia i mechanizm

Wrodzona niewydolność jajników
Patofizjologia i mechanizm

Wrodzona niewydolność jajników (Primary Ovarian Insufficiency, POI) to heterogenne zaburzenie charakteryzujące się utratą funkcji jajników przed 40. rokiem życia, z patogenezą obejmującą dysfunkcję i deplecję pęcherzyków jajnikowych. Główne mechanizmy to defekt migracji pęcherzyków, zmniejszenie liczby pierwotnych pęcherzyków, zwiększona atrezja oraz zaburzenia dojrzewania pęcherzyków. Genetyczne podłoże POI jest złożone, z około 90 genami powiązanymi z izolowanymi lub syndromicznymi postaciami, a warianty genetyczne wykrywa się u 18-23% pacjentek. Zaburzenia chromosomalne, zwłaszcza dotyczące chromosomu X (np. zespół Turnera 45,X0), występują u 10-13% kobiet z POI. Kluczowe geny to m.in. FMR1 (premutacja u 6-24% pacjentek), FOXL2, BRCA1, MCM8-MCM9, BMP15, NOBOX, FIGLA oraz FSHR, z istotną rolą w naprawie dwuniciowych pęknięć DNA (DSB) i mechanizmach takich jak rekombinacja homologiczna (HR) i niehomologiczne łączenie końców (NHEJ). Ostatnie badania wskazują na udział szlaku BNC1-NF2-Hippo-YAP-ferroptozy w patogenezie POI, co otwiera perspektywy terapeutyczne oparte na inhibitorach YAP i ferroptozy.

Patofizjologia wrodzonej niewydolności jajników

Główne mechanizmy rozwoju POI
Czynniki genetyczne w patogenezie POI
Czynniki autoimmunologiczne
Czynniki jatrogenne i środowiskowe
Molekularne mechanizmy dysfunkcji pęcherzyków
Rola niekodujących RNA w patogenezie POI
Fenotypowa zmienność POI

Konsekwencje patofizjologiczne POI
Podsumowanie patogenezy POI

Kolejne rozdziały

Patofizjologia wrodzonej niewydolności jajników

Wrodzona niewydolność jajników (Primary Ovarian Insufficiency, POI) to heterogenne zaburzenie charakteryzujące się utratą funkcji jajników przed ukończeniem 40 roku życia. Patogeneza POI jest złożona i wieloczynnikowa, a w około 90% przypadków dokładna etiologia pozostaje nieznana (idiopatyczna)¹². Aktualny stan wiedzy wskazuje na dwa główne mechanizmy prowadzące do powstania tego schorzenia: dysfunkcję pęcherzyków jajnikowych oraz ich deplecję³.

Główne mechanizmy rozwoju POI

Dysfunkcja pęcherzyków jajnikowych oznacza, że pęcherzyki pozostają w jajniku, ale proces patologiczny uniemożliwia ich prawidłowe funkcjonowanie (np. w wyniku mutacji receptora FSH). Natomiast deplecja pęcherzyków wskazuje na brak pierwotnych pęcherzyków w jajniku². W kontekście mechanizmów patogenetycznych wyróżnia się cztery główne kategorie:⁴

Defekt migracji pęcherzyków we wczesnej embriogenezie
Wczesne zmniejszenie liczby pierwotnych pęcherzyków
Zwiększona atrezja pęcherzyków
Zaburzona dojrzewanie lub rekrutacja pierwotnych pęcherzyków

⁴

Deplecja pęcherzyków stanowi główny mechanizm patogenetyczny w rozwoju POI. Rezerwa pierwotnych pęcherzyków może zostać przedwcześnie wyczerpana z powodu niskiej początkowej liczby pęcherzyków lub przyspieszonego tempa atrezji pęcherzykowej⁵. Stany patologiczne powodujące deplecję lub zmniejszenie liczby pęcherzyków mogą prowadzić do zaburzenia wysoce skoordynowanego procesu wzrostu pęcherzyków i owulacji⁵.

Czynniki genetyczne w patogenezie POI

Badania genomowe w ostatnich latach znacząco poszerzyły wiedzę na temat patogenezy POI, identyfikując około 90 genów powiązanych z izolowaną lub syndromiczną postacią POI⁶. Jednak warianty w tych znanych genach odpowiadają jedynie za niewielki odsetek pacjentek, co wskazuje na wysoką heterogenność genetyczną tego schorzenia⁶. Najnowsze badania z wykorzystaniem sekwencjonowania eksomowego wykazały, że przynajmniej 18-23% pacjentek z POI ma nieprawidłowości genetyczne⁷.

Zaburzenia chromosomalne występują u około 10-13% kobiet z POI⁸⁹. Większość z nich związana jest z nieprawidłowościami chromosomu X. Chromosomalne zaburzenia powodują POI poprzez utratę pierwotnych oocytów we wczesnym rozwoju żeńskim⁸. Przykładem jest zespół Turnera (45,X0), w którym dochodzi do wczesnej apoptozy oocytów w życiu płodowym oraz przyspieszonej deplecji oocytów we wczesnym okresie życia (przed 10 rokiem życia), co skutkuje znacznie ograniczoną rezerwą jajnikową w wieku reprodukcyjnym¹.

Oprócz nieprawidłowości chromosomalnych, warianty pojedynczych genów również mogą powodować POI¹⁰. Wśród nich zidentyfikowano geny związane z procesami krytycznymi dla zachowania funkcji jajników, takimi jak:¹¹

Różnicowanie i rozwój gonad
Replikacja i naprawa DNA
Mejoza
Oogeneza
Folikulogeneza
Sygnalizacja endokrynna
Funkcja mitochondrialna

¹¹

Szczególnie istotna jest rola genów związanych z naprawą uszkodzeń DNA, zwłaszcza dwuniciowych pęknięć DNA (DSB – Double-Strand Breaks), które naprawiane są głównie poprzez rekombinację homologiczną (HR) i niehomologiczne łączenie końców (NHEJ)¹². Uszkodzenia tych szlaków mogą prowadzić do kumulacji DSB i ostatecznie do choroby¹³.

Jednym z najlepiej poznanych genów związanych z POI jest FMR1 (Fragile X Mental Retardation 1). Premutacja w genie FMR1 jest najczęstszą pojedynczą nieprawidłowością genetyczną związaną z rozwojem POI – występuje u 12,9% do 24% kobiet z premutacją FMR1¹⁴. U kobiet z POI z prawidłowym kariotypem, 6% ma premutację w genie FMR1¹⁵. W przypadku premutacji FMR1 dochodzi do nadprodukcji nieprawidłowego mRNA FMR1 zawierającego rozszerzony region powtórzeń CGG. Uważa się, że wysokie poziomy tego mRNA są przyczyną objawów FXPOI (Fragile X-associated Primary Ovarian Insufficiency)¹⁶.

Inne geny identyfikowane w ostatnich badaniach jako istotne w patogenezie POI to m.in.:¹⁰¹⁷

FOXL2 – mutacje powodują zespół blepharophimosis, ptosis, epicanthus inversus (BPES), a POI jest częścią wariantu BPES typu I
BRCA1 – odgrywa istotną rolę w naprawie dwuniciowych pęknięć DNA; kobiety z mutacją linii zarodkowej BRCA1 mają tendencję do przedwczesnej menopauzy
Kompleks MCM8-MCM9 – odgrywa kluczową rolę w rekombinacyjnej naprawie dwuniciowych pęknięć DNA
BMP15 (bone morphogenetic protein 15) – członek nadrodziny transformującego czynnika wzrostu beta (TGF-β), zlokalizowany na krótkim ramieniu chromosomu X
NOBOX (newborn ovary homeobox gene) – gen homeoboksowy istotny w rozwoju pęcherzyków jajnikowych
FIGLA (folliculogenesis specific bHLH transcription factor) – czynnik transkrypcyjny specyficzny dla folikulogenezy
FSHR (follicle-stimulating hormone receptor) – receptor hormonu folikulotropowego

¹⁰¹⁷¹⁸

Niedawne odkrycia pokazują również, że geny zaangażowane w szlak BNC1-NF2-Hippo-YAP-Ferroptoza odgrywają istotną rolę w patogenezie POI. Deficyt BNC1 prowadzi do przedwczesnej aktywacji pęcherzyków i nadmiernej atrezji pęcherzykowej. Mechanistycznie, niedobór BNC1 wywołuje ferroptozę oocytów poprzez szlak NF2-YAP¹⁹. Odkrycia te ujawniły nowy mechanizm patologiczny POI oparty na deficycie BNC1 i sugerują, że inhibitory YAP i ferroptozy mogą być potencjalnymi celami terapeutycznymi²⁰.

Czynniki autoimmunologiczne

Mechanizmy autoimmunologiczne są zaangażowane w patogenezę 4-30% przypadków POI²¹. Dowody wskazujące na etiologię autoimmunologiczną obejmują:²¹

Obecność limfocytarnego zapalenia jajników (oophoritis)
Wykrycie przeciwciał przeciwjajnikowych
Współwystępowanie chorób autoimmunologicznych

²¹

W przypadkach, gdy POI jest związane z autoimmunologiczną niewydolnością nadnerczy, badanie histologiczne prawie zawsze potwierdza obecność autoimmunologicznego zapalenia jajników, w którym pęcherzyki są infiltrowane przez limfocyty, komórki plazmatyczne i makrofagi, które atakują głównie komórki produkujące steroidy i ostatecznie prowadzą do deplecji pęcherzyków²².

Autoimmunologiczna niewydolność jajników może występować w trzech różnych sytuacjach:²³

W powiązaniu z autoimmunologiczną chorobą nadnerczy
W powiązaniu z autoimmunologicznymi chorobami pozanadnerczowymi
Jako izolowana idiopatyczna choroba autoimmunologiczna

²³

Pacjentki z POI mają 50% szans na rozwój niewydolności nadnerczy, jeśli mają autoimmunologię nadnerczy¹⁵. Częstość występowania tych chorób u kobiet z POI jest wyższa niż w populacji ogólnej, co sugeruje, że mechanizmy autoimmunologiczne są zaangażowane w patogenezę nawet do 30% przypadków POI²⁴.

Czynniki jatrogenne i środowiskowe

Przyczyny jatrogenne POI stają się coraz bardziej powszechne wraz ze zwiększonym dostępem do opcji leczenia chirurgicznego, a także chemioterapii i radioterapii¹⁸. Chemioterapia indukuje apoptozę dojrzałych pęcherzyków jajnikowych, a badania histologiczne wykazały włóknienie, uszkodzenie naczyń i zmniejszoną liczbę pęcherzyków¹⁸.

Natychmiastowa utrata funkcji jajników po chemioterapii lub radioterapii określana jest jako ostra niewydolność jajników, która może być przejściowa¹⁵. Chociaż najwyższa częstość występowania ostrej niewydolności jajników występuje po zastosowaniu leków alkilujących lub prokarbazyny, im młodsza jest pacjentka w momencie otrzymywania chemioterapii, tym bardziej prawdopodobne jest, że niektóre pęcherzyki przeżyją¹⁵.

Prawie każda operacja miednicy, która wpływa na ukrwienie jajników, może być odpowiedzialna za rozwój POI. Rozległa lub powtarzana operacja jajników, nawet w przypadku choroby łagodnej, takiej jak endometrioza, może prowadzić do POI²⁴.

Wśród czynników środowiskowych szczególną uwagę zwraca się na dym tytoniowy. Wykazano znaczny wzrost deplecji pierwotnych pęcherzyków i apoptozy pęcherzyków antralnych po ekspozycji na dym tytoniowy²⁵. Zwiększony stres oksydacyjny, nasilona apoptoza, zmiany w relacji między komórkami ziarnistymi a oocytami, zaburzona funkcja jądrowa oocytu i naruszona integralność komórek lutealnych mogą zbiorowo przyczyniać się do zakłóceń w rozwoju pęcherzyków²⁵.

Kadm, metal ciężki obecny w dymie tytoniowym, ma biologiczny okres półtrwania wynoszący od 15 do 30 lat i jest powoli wydalany z organizmu²⁶. Kadm może powodować zaburzenia rozwoju jajników poprzez obniżenie ekspresji genu SCF/c-kit i jego powiązanych czynników mikroRNA²⁶.

Molekularne mechanizmy dysfunkcji pęcherzyków

Na poziomie molekularnym, rzadkie mutacje w genach kodujących receptory FSH i LH mogą zmieniać odpowiedź jajników na krążące gonadotropiny, prowadząc do niefunkcjonalnej tkanki jajnikowej¹. U niektórych pacjentek z POI FSH może wiązać się z miejscem receptora FSH, ale być nieaktywne. Poprzez obniżenie endogennych poziomów FSH za pomocą etynyloestradiolu (EE) lub analogu GnRH, miejsca receptorowe są wolne, a leczenie egzogennym rekombinowanym FSH aktywuje receptory, umożliwiając normalny wzrost pęcherzyków i owulację²².

Proces owulacji rozpoczyna się od wyrzutu hormonu luteinizującego (LH), który wywołuje dojrzewanie dominującego pęcherzyka Graafa z wznowieniem mejozy I. Ten dominujący pęcherzyk Graafa jest głównym źródłem estradiolu u kobiet w wieku rozrodczym. Następnie dochodzi do zatrzymania dojrzewania w metafazie II, aż do zapłodnienia oocytu²⁷. Dysfunkcja tego procesu prowadzi do braku owulacji, znikomej lub zerowej produkcji estradiolu i następstw stanu hipoestrogennego²⁷.

Coraz więcej dowodów wskazuje na związek między długowiecznością reprodukcyjną a genami szlaku odpowiedzi na uszkodzenia DNA²⁸. Uszkodzenie DNA i naprawa w komórkach ziarnistych jajnika są silnie związane z POI²⁸. Wyczerpanie oocytów z uszkodzonym DNA następuje poprzez różne mechanizmy śmierci komórkowej, takie jak apoptoza, autofagia i nekroptoza, za pośrednictwem szlaku PTEN/PI3K/AKT/FOXO3 (phosphatase and tensin homolog/phosphoinositide 3-kinase/protein kinase B/forkhead transcription factors 3)²⁸.

Geny kandydujące zidentyfikowane w ostatnich badaniach są zaangażowane w kilka procesów, które wcześniej nie były uznawane za odgrywające rolę w ludzkiej POI, takich jak specyfikacja PGC (primordial germ cells), inicjacja mejozy i metabolizm matczynego mRNA⁷. Odkrycie wariantów w PRDM1 pokazuje, że patofizjologia POI może rozpocząć się już na etapie specyfikacji PGC⁷.

Rola niekodujących RNA w patogenezie POI

Ustanowienie roli niekodujących RNA (ncRNA) w POI jest wschodzącym obszarem badań²⁹. NcRNA można podzielić na małe ncRNA (sncRNA) i długie ncRNA (lncRNA), które przyczyniają się do regulacji różnych procesów biologicznych, takich jak proliferacja i apoptoza komórek, a nie prowadzą do powstawania białek²⁹.

Fenotypowa zmienność POI

Istotną cechą POI jest jej zmienność fenotypowa. Owulacja może występować losowo i nieprzewidywalnie u pacjentek z POI²⁷. U niektórych pacjentek z samoistnym POI występuje wiele pęcherzyków jajnikowych z pozornie normalnymi oocytami, które nie rosną i nie owulują pomimo podwyższonych poziomów gonadotropin³⁰.

Kompleksowo, wyniki badań naukowych wspierają prawdopodobieństwo, że akumulacja wielu defektów genetycznych może skutkować bardziej nasilonym fenotypem⁷. W ostatnich pięciu latach badania z wykorzystaniem sekwencjonowania eksomowego zidentyfikowały wysokie wskaźniki dziedziczenia digenicznego (warianty w dwóch różnych genach), oligogenicznego (warianty w więcej niż dwóch różnych genach) i poligenicznego (warianty w wielu różnych genach) w kohortach kobiet z POI³¹.

Konsekwencje patofizjologiczne POI

Konsekwencje dysfunkcji jajników i hipoestrogenizmu mogą być poważne dla dotkniętych osób³². Następstwa POI obejmują objawy naczynioruchowe, atrofię urogenitalną, osteoporozę i złamania, choroby sercowo-naczyniowe oraz zwiększoną śmiertelność z wszystkich przyczyn³².

Środowisko hipoestrogenowe wynikające z POI może prowadzić do złego stanu kości ze zwiększonym ryzykiem złamań, zwiększonego ryzyka zdarzeń sercowo-naczyniowych i objawów menopauzalnych³³. Niskie poziomy estrogenu mogą wpływać na mięśnie wyścielające tętnice i mogą zwiększać odkładanie cholesterolu w tętnicach. Te czynniki zwiększają ryzyko miażdżycy (stwardnienia tętnic)³⁴.

Hormon estrogen pomaga utrzymać mocne kości. Bez wystarczającej ilości estrogenu, kobiety z POI często rozwijają osteoporozę – chorobę kości, która powoduje słabe, kruche kości, które są bardziej podatne na złamania³⁴.

Zmiany hormonalne spowodowane przez POI mogą przyczyniać się do lęku lub prowadzić do depresji³⁴. Poradnictwo psychologiczne powinno być oferowane, ponieważ zgłaszano obniżoną samoocenę i stres emocjonalny po zdiagnozowaniu POI¹⁵.

Podsumowanie patogenezy POI

Pomimo znacznych postępów w zrozumieniu patogenezy POI, w około 90% przypadków dokładna przyczyna pozostaje nieznana. Badania identyfikują coraz więcej czynników genetycznych, autoimmunologicznych i środowiskowych przyczyniających się do rozwoju tej choroby. Odkrycia te nie tylko poszerzają nasze zrozumienie fizjologii jajników, ale również mogą prowadzić do nowych strategii diagnostycznych i terapeutycznych dla kobiet dotkniętych POI.

Bardzo istotne jest, że badania naukowe zidentyfikowały nowe mechanizmy molekularne zaangażowane w patogenezę POI, w tym szlaki związane z naprawą uszkodzeń DNA, odpowiedzią na stres oksydacyjny, ferroptczą śmiercią komórek, a także rolę niekodujących RNA. Te odkrycia otwierają nowe możliwości dla celowanych interwencji terapeutycznych w przyszłości.

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Materiały źródłowe

#1 Primary Ovarian Insufficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/136054
Primary ovarian insufficiency is thought to arise from either follicular dysfunction or follicular depletion. However, the exact mechanisms in which POI develops remain unknown. Approximately 90% of all diagnosed cases of spontaneous POI do not have a determined underlying etiology. […] 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. 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. 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.
#2 Primary Ovarian Insufficiency
https://pmc.ncbi.nlm.nih.gov/articles/PMC2762081/
Primary ovarian insufficiency occurs through two major mechanisms: follicle dysfunction and follicle depletion. Follicle dysfunction indicates that follicles remain in the ovary, but a pathologic process prevents their normal function (e.g., as a result of an FSH-receptor mutation). Follicle depletion indicates that no primordial follicles remain in the ovary. This condition may be due to the failure of an adequate initial pool of primordial follicles to be established in utero, an accelerated expenditure of follicles, or autoimmune or toxic destruction of follicles. […] In 90% of the cases of primary ovarian insufficiency, the cause remains a mystery. Spontaneous 46,XX primary ovarian insufficiency can occasionally occur as part of a syndrome. In addition, several single genes (e.g., bone morphogenetic protein 15 [BMP15], diaphanous homolog 2 [DIAPH2], and inhibin alpha subunit [INHA]) have been associated with nonsyndromic primary ovarian insufficiency, but their clinical relevance is not clear. Structural abnormalities in the X chromosome apart from specific gene mutations may also be a cause.
#3 Factors leading to primary ovarian insufficiency: a literature overview – GREM – Gynecological and Reproductive Endocrinology & Metabolism
https://gremjournal.com/journal/02-2021/factors-leading-to-primary-ovarian-insufficiency-a-literature-overview/
Premature ovarian insufficiency (POI) is a disease characterized by oligomenorrhea, hypoestrogenism and elevated gonadotropin levels that occurs in women younger than 40 years of age. […] Depending on the cause, POI can be classified as primary (spontaneous) or secondary (iatrogenic). […] From a pathogenetic point of view, primary ovarian insufficiency occurs through two major mechanisms: follicle dysfunction and follicle depletion. […] The aims of this review are to examine the factors that can determine or contribute to primary POI, and to discuss the developments that are likely to be significant in the future, including the desirable avenues of future research. […] In about 75% of POI cases, however, the cause remains unknown. […] Early diagnosis is key in the management of young patients with primary POI, as it allows the establishment of a proper hormone replacement therapy.
#4 Primary ovarian insufficiency – Wikipedia
https://en.wikipedia.org/wiki/Primary_ovarian_insufficiency
Primary ovarian insufficiency (POI), also called premature ovarian insufficiency and premature ovarian failure, is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular (egg producing area) dysfunction or early loss of eggs. […] The causes of POI are heterogeneous and are unknown in 90% of cases. It can be associated with genetic causes, autoimmune disease, enzyme deficiency, infection, environmental factors, radiation, or surgery in 10%. […] The pathogenic mechanisms of POI are highly heterogeneous and can be divided into four major categories: follicular migration defect early in embryogenesis; an early decrease in the primordial follicles; increased follicular death; and altered maturation or recruitment of primordial follicles.
#5 Ovarian Insufficiency: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/271046-overview
Primary ovarian insufficiency (POI) (premature ovarian failure, premature menopause, or early menopause) is a condition characterized by amenorrhea, hypoestrogenism, and elevated serum gonadotropin levels in women younger than 40 years. […] The pathogenesis of spontaneous POI/POF in most cases is unknown. Two mechanisms are presumed to play a role: follicle depletion and follicle dysfunction. […] Follicle depletion is a major pathogenetic mechanism for development of POI/POF. […] Pathological conditions that cause depletion or a reduction of the follicle number may lead to a disruption of the highly coordinated process of follicular growth and ovulation. […] The ovarian follicle reserve can be depleted prematurely because of a low initial number or an accelerated rate of follicle atresia.
#6 Landscape of pathogenic mutations in premature ovarian insufficiency | Nature Medicine
https://www.nature.com/articles/s41591-022-02194-3
Premature ovarian insufficiency (POI) is a major cause of female infertility due to early loss of ovarian function. POI is a heterogeneous condition, and its molecular etiology is unclear. To identify genetic variants associated with POI, here we performed whole-exome sequencing in a cohort of 1,030 patients with POI. We detected 195 pathogenic/likely pathogenic variants in 59 known POI-causative genes, accounting for 193 (18.7%) cases. […] Recent advances in high-throughput sequencing have greatly expanded understanding of the pathogenesis of POI, with approximately 90 genes now linked to either isolated or syndromic POI. However, variants in these known genes account for only a small fraction of patients, indicating the high genetic heterogeneity of POI. […] Identifying the molecular basis of POI is, thus, of paramount importance for investigating therapeutic targets, such as in vitro activation, and for guiding genetic counseling or pregnancy planning.
#7 Landscape of pathogenic mutations in premature ovarian insufficiency | Nature Medicine
https://www.nature.com/articles/s41591-022-02194-3
The substantial contribution of genetic variants to POI in this cohort should prompt reconsideration of routine mutation screening in diagnosed patients, which is not currently recommended in POI management guidelines due to the presumed rarity of monogenic causes. […] The findings of this large cohort investigation indicate that at least 18~23% of patients have genetic abnormalities, thus supporting implementation of routine clinical WES in POI. […] The novel candidate genes identified in this study are involved in several processes that were previously unrecognized to play a role in human POI, such as PGC specification, meiosis initiation and maternal mRNA metabolism. […] The discovery of variants in PRDM1 demonstrates that the pathophysiology of POI may begin as early as PGC specification. […] Comprehensively, our findings support the likelihood that the accumulation of multiple genetic defects may result in a more severe phenotype.
#8 Selected Genetic Factors Associated with Primary Ovarian Insufficiency
https://www.mdpi.com/1422-0067/24/5/4423
The prevalence of POI caused by chromosomal abnormalities varies in different populations, with the values ranging from approximately 10% to 13%. […] Chromosomal disorders cause POI via the depletion of primordial oocytes during early female development. […] However, the mechanism involved in the loss of oocytes is not clearly understood. […] A number of studies have established a relationship between X chromosomal structural disorders (mainly X chromosomal deletions), X-autosomal translocations, and POI. […] Moreover, many POI candidate genes on the X chromosome can be found by analyzing the X-autosome translocations, some of which are introduced below. […] Autosomal translocations, microdeletions, specific gene mutations, epistasis, and epigenetics associated with autosomal genes are all responsible for POI.
#9 Premature Ovarian Insufficiency | IntechOpen
https://www.intechopen.com/chapters/63848
Most cases of spontaneous POI are idiopathic despite the diagnostic advances but may be also due to genetic causes, autoimmune disorders, metabolic dysfunction, enzyme deficiencies, toxins, or infections. […] The normal ovarian function requires the presence of many intact genes functionally normally and in a coordinated fashion. Chromosomal abnormalities are found in around 10-12% of women with POI, of which the majority is X chromosomal abnormalities. […] Anti-ovarian antibodies are reported in POI by several studies, but their specificity and pathogenic role are questionable. Autoimmune diseases are estimated to be involved in the pathogenesis of up to 5% of POI cases. […] A number of inherited enzymatic pathway disorders have been associated with ovarian follicular dysfunction leading to POI such as galactose-1-phosphate uridylyltransferase deficiency (galactosemia), carbohydrate-deficient glycoprotein deficiency, 17-hydroxylase/17,20 desmolase deficiency, and aromatase mutations where there is biochemical damage of the ovary and autoimmune regulator which triggers autoimmune damage.
#10 Selected Genetic Factors Associated with Primary Ovarian Insufficiency
https://www.mdpi.com/1422-0067/24/5/4423
Aside from chromosomal abnormalities, single gene variations can also cause POI. […] The classical candidate gene approach is based on genes with known functions and experimental models in mice. […] Using this method, many genes, such as BMP15, NOBOX, and FMR1, have been discovered. […] The associated genes identified in the last 10 years are classified according to the biological processes they participate in. […] A normal oocyte reserve is essential for females of reproductive age to give birth to a healthy baby. […] However, if any error occurs during meiosis, DNA replication, or DNA repair, the genetic information is negatively affected, leading to germ cell apoptosis and infertility. […] Therefore, collecting and investigating the genes involved in the critical processes of meiosis, DNA replication, and DNA repair is beneficial for obtaining a better understanding of POI.
#11 Premature ovarian insufficiency — Knowledge Hub
https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/premature-ovarian-insufficiency/
Premature ovarian insufficiency is the term used to describe ovarian dysfunction arising from an inherent defect within the ovary itself. […] A proportion of POI is genetically mediated. Within clinical contexts, approximately 5%10% of women with POI have a causative genetic mechanism identified. These include sex chromosome aneuploidies, such as Turner syndrome, as well as pathogenic variants in autosomal and sex chromosome genes. […] Genetically, POI is remarkably heterogeneous. Next-generation sequencing studies have related pathogenic variants in more than 100 genes to the molecular pathogenesis of both syndromic and non-syndromic POI. […] The genes involved in POI relate to complex cellular and reproductive processes, including gonadal differentiation and development, DNA replication and repair, meiosis, oogenesis, folliculogenesis, endocrine signalling and mitochondrial function.
#12 DNA double-strand break genetic variants in patients with premature ovarian insufficiency | Journal of Ovarian Research | Full Text
https://ovarianresearch.biomedcentral.com/articles/10.1186/s13048-023-01221-2
Notably, genetic factors account for 7% to 30% of all causative factors of POI and have been a hotspot for POI research. […] Among them, DNA double-strand breaks (DSB), which are mainly repaired by homologous recombination (HR) and non-homologous end joining (NHEJ), are the most devastating type of DNA damage. […] Mutations in key genes during this process can affect the normal physiological function of the ovary and can easily lead to follicular atresia or oocyte apoptosis, leading to POI. […] This area of research will potentially lead to new ideas for the prevention of POI, early detection of POI and treatment of POI at the genetic level, further contributing to the knowledge and understanding of female reproductive health. […] The correct production of programmed DSBs in meiosis, is a prerequisite for homologous chromosomal gene recombination and is essential for maintaining ovarian function.
#13 DNA double-strand break genetic variants in patients with premature ovarian insufficiency | Journal of Ovarian Research | Full Text
https://ovarianresearch.biomedcentral.com/articles/10.1186/s13048-023-01221-2
The last process is the synthetic repair of DNA and intermediate resolution, which requires the removal of RAD51 (and DMC1) from the D-loop, followed by the synthesis of the complementary strand from the 3′ end of the invasion strand using DNA polymerase. […] Once the enzymes or proteins related to the DSB repair pathway are missing or abnormal in the body, it may cause errors in repair, leading to the accumulation of DSBs and eventually to disease. […] The specific HR and NHEJ processes are shown in Figure A and B. […] The specific mechanisms of ERCC6 gene and CSB-PGBD3 fusion gene mutations in the pathogenesis of POI should be further investigated in the future. […] This review summarizes the DSB formation and damage repair genes associated with the pathogenesis of POI that have been identified in recent years, including genes that have widely been acknowledged to cause POI, as well as candidate genes that are less significant in the development of POI and have not been confirmed to cause POI.
#14 Primary Ovarian Insufficiency: Time to Diagnosis and a Review of Current Literature
https://www.imrpress.com/journal/CEOG/49/6/10.31083/j.ceog4906129/htm
Primary ovarian insufficiency occurs because of accelerated depletion of follicles via apoptosis or a disruption in normal follicular function. Follicular dysfunction may be due to a number of causes, including disruption in follicular response to gonadotropins (e.g., due to FSH or luteinizing hormone (LH) receptor mutations), steroidogenic enzyme deficiency, or autoimmune lymphocytic infiltration of the theca layer of antral follicles. […] However, regarding possible etiologies that contribute to the loss of follicular function, idiopathic causes make up 74â90% of cases. Follicular dysfunction or loss of ovarian follicles interrupts the menstrual cycle, resulting in oligo/amenorrhea, reduced fertility, and accompanying menopausal symptoms experienced by women with POI. […] About 10â20% of POI cases can be attributed to genetic causes, thus many efforts have been made to identify candidate genes associated with disease onset. Since no single gene has been identified as the sole cause of POI, it is theorized that POI is the result of multiple gene mutationsâFMR1 being among the many genes that has been linked to the development of POI. A premutation in the FMR1 gene is the most common single gene abnormality associated with the development of POIâ12.9% to 24% of women with the FMR1 premutation experience primary ovarian insufficiency. Chromosomal abnormalities are a more common etiology of POI than single gene mutations, with Turner Syndrome making up most of the cases.
#15 Primary Ovarian Insufficiency in Adolescents and Young Women | ACOG
https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2014/07/primary-ovarian-insufficiency-in-adolescents-and-young-women
Fragile X syndrome is the most common form of hereditable mental retardation. […] Among females with primary ovarian insufficiency and a normal karyotype, 6% have a premutation in the FMR1 gene. […] The goals of hormonal therapy extend beyond simply symptom relief to levels that support bone, cardiovascular, and sexual health. […] Patients with primary ovarian insufficiency are estrogen deficient. […] Primary ovarian insufficiency increases the risk of bone loss, CV disease, and endocrine disorders. […] Patients with primary ovarian insufficiency also have a 50% chance of developing adrenal insufficiency if they have adrenal autoimmunity. […] Psychologic counseling also should be offered because impaired self-esteem and emotional distress have been reported after diagnosis of primary ovarian insufficiency. […] Once primary ovarian insufficiency is diagnosed, patients should be evaluated at least annually.
#15 Primary Ovarian Insufficiency in Adolescents and Young Women | ACOG
https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2014/07/primary-ovarian-insufficiency-in-adolescents-and-young-women
ABSTRACT: Primary ovarian insufficiency is the depletion or dysfunction of ovarian follicles with cessation of menses before age 40 years. […] Primary ovarian insufficiency is the depletion or dysfunction of ovarian follicles with cessation of menses before age 40 years, and it has previously been referred to as premature menopause or primary ovarian failure. […] Approximately 4% of women who have primary ovarian insufficiency will have adrenal or ovarian antibodies, which suggests an autoimmune mechanism for disease. […] The immediate loss of ovarian function after chemotherapy or radiation therapy is termed acute ovarian failure, which may be transient. […] Although the highest incidence of acute ovarian failure occurs after the use of alkylating agents or procarbazine, the younger the patient at the time of receiving the chemotherapy, the more likely it is that some follicles will survive.
#16 Fragile X-associated primary ovarian insufficiency: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/fragile-x-associated-primary-ovarian-insufficiency/
Fragile X-associated primary ovarian insufficiency (FXPOI) is a condition that affects women and is characterized by reduced function of the ovaries. […] The reduction in ovarian function caused by FXPOI results in low levels of the hormone estrogen, which leads to many of the common signs and symptoms of menopause, such as hot flashes, insomnia, and thinning of the bones (osteoporosis). […] Mutations in the FMR1 gene increase a woman’s risk of developing FXPOI. […] Women with FXPOI have a mutation in which a DNA segment, known as a CGG triplet repeat, is expanded within the FMR1 gene. […] For unknown reasons, the premutation leads to the overproduction of abnormal FMR1 mRNA that contains the expanded repeat region. […] Researchers believe that the high levels of mRNA cause the signs and symptoms of FXPOI. […] It is thought that the mRNA attaches to other proteins and keeps them from performing their functions. […] An increased risk of developing FXPOI is inherited in an X-linked dominant pattern.
#17 Primary ovarian insufficiency – Wikipedia
https://en.wikipedia.org/wiki/Primary_ovarian_insufficiency
Genetic associations include genetic disorders, autoimmune diseases, enzyme defects, and resistant ovaries. […] Mutations in FOXL2 cause blepharophimosis, ptosis, epicanthus inversus syndrome (BPES). Premature ovarian failure is part of the BPES Type I variant of the syndrome but not of the BPES Type II variant. […] BRCA1 protein plays an essential role in the repair of DNA double-strand breaks by homologous recombination. Women with a germline BRCA1 mutation tend to have premature menopause as evidenced by the final amenorrhea appearing at a younger age. […] Impairment of the repair of DNA double-strand breaks due to a BRCA1 defect leads to premature ovarian aging in both mice and humans. […] In addition to BRCA1, the MCM8-MCM9 protein complex also plays a crucial role in the recombinational repair of DNA double-strand breaks.
#18
https://journals.lww.com/jomh/fulltext/2015/06040/premature_ovarian_insufficiency__pathogenesis_and.1.aspx
Fragile X syndrome is an X-linked dominant genetic condition associated with POI. […] Bone morphogenetic protein 15 is a member of the transforming growth factor beta (TGF-) superfamily and is located on the short arm of the X chromosome. […] There is a strong association between POI and autoimmune dysfunction. […] Iatrogenic causes of POI are becoming more common as access increases to surgical management options as well as chemotherapy and radiotherapy. […] Chemotherapy induces apoptosis of mature ovarian follicles, and histological studies have shown fibrosis, vascular damage, and reduced follicle numbers. […] Women known to be carriers of the BRCA genes are presenting in increasing numbers for prophylactic surgery, and some forms of gynecological surgery considered, in the past, to be minor are now being reported to have greater consequences on ovarian function.
#19 ZJU scientists discover new pathologic mechanism of primary ovarian insufficiency
https://www.zju.edu.cn/english/2022/1013/c19573a2646203/page.htm
Primary ovarian insufficiency (POI) is a clinical syndrome defined as premature exhaustion of the resting pool of primordial follicles before the age of 40 years and characterized by oligo-/amenorrhea for at least 4 months with elevated gonadotrophins. […] The pathologic mechanism of POI based on oocyte ferroptosis was revealed, subverting the classical cognition. […] In this study, Prof. ZHANG Dan’s research team focused on the underlying mechanism of BNC1 targeted mutation leading to POI, and found that BNC1 played key roles in ovarian reserve and maintaining lipid metabolism and redox homeostasis in oocytes during follicle development. Deficiency of BNC1 resulted in premature follicular activation and excessive follicular atresia. Mechanistically, BNC1 deficiency triggered oocyte ferroptosis via the NF2-YAP pathway.
#20 ZJU scientists discover new pathologic mechanism of primary ovarian insufficiency
https://www.zju.edu.cn/english/2022/1013/c19573a2646203/page.htm
These findings uncovered a new pathologic mechanism of POI based on BNC1 deficiency, and suggested YAP and ferroptosis inhibitors as potential therapeutic targets for POI. Just as Prof. ZHANG Dan says, this study clarifies the role and mechanism of BNC1-NF2-Hippo-YAP signaling -Ferroptosis axis in POI, and establishes a new potential treatment method for POI based on ferroptosis, which provides a new theoretical basis for the clinical precise prevention and treatment of primary ovarian insufficiency.
#21 Pathogenesis and Causes of Premature Ovarian Failure: An Update
https://www.ijfs.ir/article_45084.html
Some cases of POF may be due to an abnormal self-recognition by the immune system. […] The exact mechanism remains obscure; probably the genetic or environmental factors initiate the immune response. […] Autoimmune mechanisms are involved in the pathogenesis of 4-30% of POF cases. […] The evidences for an autoimmune etiology are: Presence of lymphocytic oophoritis, Demonstration of ovarian autoantibodies, Associated autoimmune disorders. […] The published incidence of antiovarian antibodies in patients with POF ranges widely due to the heterogeneity of investigation methods, multiple ovarian antibody targets, the transient appearance of antiovarian antibodies, different stages of disease, as well as variations in antibody test format and antigen presentation. […] In autoimmune ovarian failure, the elevated serum gonadotropin hormones result from the dysfunction of the ovarian follicles rather than follicular depletion. […] In conclusion, although in the majority of POF cases the underlying cause is not identified, several etiological factors can affect normal ovarian function and lead to permanent or transient ovarian failure.
#22 Primary ovarian insufficiency – Wikipedia
https://en.wikipedia.org/wiki/Primary_ovarian_insufficiency
Genetic causes such as Turner syndrome have initial ovarian development but then ovaries degenerate rapidly during prenatal life, often leading to gonadal dysgenesis with streak ovaries. […] In those cases where POI is associated with adrenal autoimmunity, histological examination almost always confirms the presence of an autoimmune oophoritis in which follicles are infiltrated by lymphocytes, plasma cells, and macrophages that attack mainly steroid-producing cells and eventually result in follicular depletion. […] In some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ethinylestradiol (EE) or with a GnRH-a the receptor sites are free and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur.
#23 Primary Ovarian Insufficiency | GLOWM
https://www.glowm.com/section-view/heading/Primary%20Ovarian%20Insufficiency/item/755
Primary ovarian insufficiency (POI), also known as premature ovarian failure, premature menopause, hypergonadotropic amenorrhea, hypergonadotropic hypogonadism, and ovarian insufficiency, refers to the loss of ovarian function before the age of 40 years. The condition may be developed as a result of many pathogenic mechanisms such as chromosomal or genetic abnormalities, autoimmune, infectious, or iatrogenic causes. In 90% of cases no cause is found and they are classified as idiopathic. […] POI may be developed as a result of many pathogenic mechanisms such as chromosomal or genetic abnormalities, autoimmune, infectious, or iatrogenic causes. […] Autoimmune diseases are characterized by the presence of organ and non-organ specific autoantibodies. Autoimmune ovarian insufficiency can be present in three different situations: (1) associated with adrenal autoimmunity, (2) associated with non-adrenal autoimmunity, and (3) isolated idiopathic autoimmunity.
#24 Primary Ovarian Insufficiency | GLOWM
https://www.glowm.com/section-view/heading/Primary%20Ovarian%20Insufficiency/item/755
The presence of these diseases in women with POI is higher than in the general population, suggesting that autoimmune mechanisms are involved in the pathogenesis of up to 30% of POI cases. […] Almost any pelvic surgery that affects the ovarian blood supply can be responsible for the development of POI. Extensive or repeated ovarian surgery, even for a benign disease such as endometriosis, can be responsible for POI. […] The incidence of amenorrhea has been reported to vary between 40% and 68% after anticancer therapy. The frequency of ovarian failure seems to depend on the type, dose, and duration of the therapy. […] Mumps oophoritis has been considered to be a cause of POI.
#25 Premature ovarian insufficiency: a review on the role of tobacco smoke, its clinical harm, and treatment | Journal of Ovarian Research | Full Text
https://ovarianresearch.biomedcentral.com/articles/10.1186/s13048-023-01330-y
Studies have indicated a significant increase in primordial follicle depletion and antral follicle apoptosis after exposure to tobacco smoke. […] Increased oxidative stress, heightened apoptosis, alterations in the relationship between granulosa cells and oocytes, impaired oocyte nuclear function, and compromised luteal cell integrity may collectively contribute to disruptions in follicular development, possibly representing the mechanisms behind tobacco-induced damage to reproductive function. […] The literature suggests that increased smoking is associated with early menopause, and that women who smoke enter menopause one year earlier than non-smoking women. […] Smoking exposure has been linked to a reduction in the follicle reserve in ovaries and alterations in estrus status and serum hormone levels.
#26 Premature ovarian insufficiency: a review on the role of tobacco smoke, its clinical harm, and treatment | Journal of Ovarian Research | Full Text
https://ovarianresearch.biomedcentral.com/articles/10.1186/s13048-023-01330-y
The occurrence of premature menopause may be related to the amount of smoking, and the sooner women quit smoking, the more likely they are to avoid early menopause. […] Cadmium has a biological half-life as long as 15 to 30 years and is slowly excreted from the body. […] Cadmium can cause ovarian development disorders in rats by downregulating the expression of the SCF/c-kit gene and its related microRNA factors. […] Benzo[a]pyrene can be detected in human serum and follicular fluid. […] The study revealed that the concentration of benzo[a]pyrene (B[a]P) was negatively correlated with the level of E2 in the medium. […] Nicotine exhibits a certain degree of anti-estrogenic effects, further disrupting the balance of reproductive and hormonal systems, and reducing the likelihood of successful pregnancy in both healthy women and those undergoing assisted reproduction.
#27 Primary Ovarian Insufficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/136054
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. Then, the cessation of maturation at metaphase II occurs until the oocyte is fertilized. 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.
#28
https://link.springer.com/article/10.1007/s00109-021-02055-5
Primary ovarian insufficiency (POI) is defined as a reduction in ovarian function before the expected age of menopause. […] The potential etiologies of POI include chromosomal abnormalities and genetic mutations, autoimmune factors, and iatrogenic causes, including surgery, chemotherapy, and radiation therapy. […] A major association is suggested to exist between reproductive longevity and the DNA damage pathway response genes. […] DNA damage and repair in ovarian granulosa cells is strongly associated with POI. […] Depletion of oocytes with damaged DNA occurs through different cell death mechanisms, such as apoptosis, autophagy, and necroptosis, mediated by the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/forkhead transcription factors 3 (FOXO3) pathway. […] The aim of this review is to summarize the pathogenic mechanisms that involve cell death and DNA damage and repair pathways and to discuss the stem cell-based therapies as potential therapeutic options for this gynecologic pathology.
#29 Selected Genetic Factors Associated with Primary Ovarian Insufficiency
https://www.mdpi.com/1422-0067/24/5/4423
Establishing the role of non-coding RNAs (ncRNAs) in POI is an emerging research area. […] NcRNAs can be divided into small ncRNAs (sncRNAs) and long ncRNAs (lncRNA), and they contribute to regulating various biological processes, such as cell proliferation and apoptosis, rather than giving rise to proteins. […] These findings clearly indicate that examining various genetic factors is crucial in determining the underlying etiologies of idiopathic POI cases.
#30 Ovarian Insufficiency: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/271046-overview
Accelerated follicle atresia or destruction can result from one of the following: X chromosome monosomy/aneuploidy or mosaicism (as observed in Turner syndrome or some cases with 47,XXX karyotype). […] The genes and chromosome regions implicated in the development of POI/POF are as follows: X chromosome genes: Multiple X chromosome genes are involved in regulating female fertility and reproductive lifespan and may be involved in the pathogenesis of ovarian failure. […] Some patients with spontaneous POI/POF have numerous ovarian follicles with seemingly normal oocytes that fail to grow and ovulate in the presence of elevated gonadotropins. […] The immune system may play a role in some cases of POI/POF. […] A true cause and effect relationship between POI/POF and infection has not been established.
#31 Premature ovarian insufficiency — Knowledge Hub
https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/premature-ovarian-insufficiency/
Established autosomal recessive inheritance, particularly in meiosis-related DNA repair genes, have been identified in cases of POI. […] As well as monogenic inheritance, exome sequencing studies over the last five years have identified high rates of digenic inheritance (variants in two different genes are involved), oligogenic inheritance (variants in more than two different genes are involved) and polygenic inheritance (variants in many different genes are involved) in cohorts of women with POI.
#32 Hormone Therapy in Primary Ovarian Insufficiency | ACOG
https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/05/hormone-therapy-in-primary-ovarian-insufficiency
Regardless of the underlying cause of primary ovarian insufficiency, the consequences of ovarian dysfunction and hypoestrogenism can be dire for affected individuals. […] The sequelae of primary ovarian insufficiency include vasomotor symptoms, urogenital atrophy, osteoporosis and fracture, cardiovascular disease, and increased all-cause mortality. […] The results from the Womens Health Initiative trials related to menopause therapy are not applicable to young women with primary ovarian insufficiency whose exposure to physiologic estrogen has been withdrawn prematurely. […] The focus of this Committee Opinion is to review the medical and psychosocial risks facing women with primary ovarian insufficiency and to discuss the various HT treatment options available. […] Primary ovarian insufficiency is a pathologic condition that should not be considered a hastening of natural menopause. […] Although women with primary ovarian insufficiency share common health risks with naturally menopausal women, the approach to health maintenance in these women is distinct. […] The approach to HT for primary ovarian insufficiency is full replacement doses of hormone for long-term treatment.
#33 Pathophysiology and management of classic galactosemic primary ovarian insufficiency in: Reproduction and Fertility Volume 2 Issue 3 (2021)
https://raf.bioscientifica.com/view/journals/raf/2/3/RAF-21-0014.xml
The hypoestrogenic environment resulting from POI can result in poor bone health with an increased risk of fracture, heightened risk of cardiovascular events, and menopausal symptoms. […] Hormone replacement therapy (HRT) with estrogen and progesterone is the mainstay treatment for patients with POI. […] Increasing evidence in CG POI suggests female infants have normal-appearing ovaries at birth that become damaged over time. […] The trajectory of gonadotrophins to mirror menopausal levels throughout childhood into adolescence can further corroborate the biopsy/ultrasounds and suggest a progression of ovarian failure; although evidence of abnormal gonadotrophin levels have been seen as early as nine months in galactosemia. […] Our data revealed nine of 11 patients with evidence of POI including abnormal hormonal values.
#34 Primary Ovarian Insufficiency | POI | MedlinePlus
https://medlineplus.gov/primaryovarianinsufficiency.html
Primary ovarian insufficiency (POI) is related to problems with the follicles. Follicles are small sacs in your ovaries. Your eggs grow and mature inside them. One type of follicle problem is that you run out of working follicles earlier than normal. Another is that the follicles are not working properly. In most cases, the cause of the follicle problem is unknown. But sometimes the cause may be: […] In about 90% of cases, the exact cause of POI is unknown. […] Research shows that POI is related to problems with the follicles. […] Certain changes to genes and genetic conditions put women at higher risk for POI. For example, women with Fragile X syndrome or Turner syndrome are at higher risk. […] Hormonal changes caused by POI can contribute to anxiety or lead to depression. […] Lower levels of estrogen can affect the muscles lining the arteries and can increase the buildup of cholesterol in the arteries. These factors increase your risk of atherosclerosis (hardening of the arteries). […] The hormone estrogen helps keep bones strong. Without enough estrogen, women with POI often develop osteoporosis. It is a bone disease that causes weak, brittle bones that are more likely to break.