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Abstract

Menstrual irregularities and abnormal uterine bleeding have been increasingly reported following severe acute respiratory syndrome coronavirus 2 infection, likely due to viral-induced endocrine disruption and immune dysregulation. A woman in her late 30s, with previously regular menses, developed persistent abnormal uterine bleeding after recovering from coronavirus disease 2019. Lab work-up over the next 2 years demonstrated high follicle-stimulating hormone, low anti-Müllerian hormone, low estrogen, and borderline antinuclear antibody titers. A pelvic ultrasound showed low antral follicle count, and she had challenges with fertility preservation. The patient was suspected of having an exaggerated immune reaction to severe acute respiratory syndrome coronavirus 2 infection with her strong family history of autoimmune disease and borderline antinuclear antibody, which may have led to an autoimmune-induced premature ovarian insufficiency. This case highlights the need to recognize post-viral menstrual irregularities and endocrine dysfunction as a potential consequence of coronavirus disease 2019. Clinicians should consider postinfectious endocrine disturbances in patients with new-onset abnormal uterine bleeding or infertility and evaluate for immune-mediated mechanisms when appropriate. Further research is needed to elucidate the long-term impact of coronavirus disease 2019 on reproductive health.

Keywords

long COVID premature ovarian insufficiency abnormal uterine bleeding infertility case report

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in 2019 as the causative agent of coronavirus disease 2019 (COVID-19). While the acute effects of COVID-19 are well-documented, the long-term effects, collectively referred to as “long COVID,” encompass a wide range of persistent symptoms affecting multiple organ systems with varying severity and duration.^1,2 Common long COVID symptoms include dyspnea, exercise intolerance, headache, fatigue, attention disorders, and hair loss.^1,2 However, less well-known sequelae of long COVID have also been documented, including effects on the female reproductive system.³ Case reports have reported menstrual cycle irregularities, premenstrual syndrome symptoms, worsening endometriosis, and premature ovarian insufficiency (POI) following COVID-19,⁴ although research on this area remains limited.⁵

POI is defined as the loss of normal ovarian function before the age of 40, which affects 1%–4% of women.^6,7 Per the European Society of Human Reproduction and Embryology (ESHRE) guidelines, POI is characterized by amenorrhea or oligomenorrhea for at least 4 months, in addition to elevated levels of follicle-stimulating hormone (FSH) of >25 mIU/mL on two occasions 4 weeks apart.^8–10 Fluctuating ovarian activity may occur, which can result in variable FSH concentrations, including alternating from normal to abnormal levels.^9,10 Low estrogen is not required as part of the diagnostic criteria; however, this provides additional confirmation of POI in combination with an elevated FSH.^9,10

The etiology of POI is heterogeneous, including genetic factors, infections, autoimmune conditions, metabolic disorders, lysosomal storage diseases, and iatrogenic causes (i.e., chemotherapy or radiation). However, the majority of POI cases are spontaneous, with no identifiable cause.⁸ Clinical symptoms may include hot flashes, night sweats, dyspareunia, sleep disturbance, and vulvovaginal atrophy as a result of estrogen deficiency, but these symptoms are not required for diagnosis as some women have intermittent ovarian function.¹¹ Long-term consequences of POI include reduced fertility, osteoporosis,¹² cardiovascular diseases,¹³ and dementia or cognitive decline.¹⁴ Early diagnosis of this condition is essential as hormone replacement therapy is recommended to mitigate long-term effects of POI and preserve fertility.

Importantly, health care providers need to be aware that infections such as SARS-COV-2 can affect women’s reproductive health.¹⁵ Here, we present a case of a young female who developed abnormal uterine bleeding (AUB) and infertility with concerns for POI following COVID-19.

Case presentation

A nulligravid (G0P0000) female in her late 30s presented with AUB and a detailed history of menstrual irregularities after COVID-19 diagnosis. The patient reported that she had previously had regular menstrual cycles. Past medical history included hyperlipidemia, melanoma in situ of lower leg (status post-excision), history of atypical nevi (status post-removal), and anxiety. Family history was significant for an aunt with ovarian cancer, aunt with type 1 diabetes mellitus, and mother with pernicious anemia and polyglandular autoimmune syndrome type 2 with Hashimoto’s thyroiditis and type 1 diabetes mellitus. Menarche occurred at age 13. The patient had no history of sexually transmitted infections or abnormal pap smears. Her occupation was an engineer, and she had been exposed to environmental toxins, including fluorinated solvents and oil spills.

She had two COVID-19 vaccinations in April 2021. She recalled experiencing an increased frequency of menstrual bleeding, with a short interval between cycles occurring <3 weeks apart, after her second vaccine dose, which then normalized. She also reported that a non-tender cyst-like structure formed in her left arm following the vaccination.

She was in her typical state of health until July 2022, when she reported symptoms of sore throat, fatigue, cough, and fever and tested positive for COVID-19. The symptoms resolved by the time she was done with quarantine (within 10 days). She subsequently went on vacation, including strenuous activities and hiking, without any concerns. Three months later, however, she reported having another episode of two menstrual cycles per month and multiple “flooding experiences.” In one instance, she “bled out” while riding a bicycle (tampon soaked within 30 min of placement).

Her menses varied between 7 and 50 days, and she was prescribed oral contraceptive pills (OCPs) by her primary care provider. After initiating combined OCPs, her first menstrual cycle was normal, the next cycle was 21 days, and subsequent cycle frequencies normalized. During her cycles, she would require tampon changes every 2–3 h during heavy flow and every 5–6 h when lighter. Clots were passed during menses as well. She was referred to a gynecologist whose physical examination of the patient was normal, and who discussed the option of hysterectomy or referral to a fertility specialist. A pelvic ultrasound revealed she had a low antral follicle count. Initial laboratory tests showed a low normal anti-Müllerian hormone (AMH), elevated FSH, normal thyroid-stimulating hormone, negative thyroid peroxidase (TPO) antibodies, and normal hemoglobin A1c (Table 1). Subsequent serum studies showed fluctuations in estradiol, with one laboratory test showing undetectable levels. Due to her family history, she underwent genetic testing, which was negative for BRCA mutations.

Table 1.

Serum labs collected over 2 years during menstrual cycle irregularities.

Date	Lab	Value	Female reference range
Year 1	FSH	15.9 mIU/mL	Normal menstruation^a: Follicular phase: 2.5–10.2 mIU/mL Midcycle: 3.4–33.4 mIU/mL Luteal phase: 1.5–9.1 mIU/mL Post-menopausal: 23.0–116.3 mIU/mL Pregnancy: <0.3 mIU/mL
	LH	8.87 mIU/mL	Normal menstruation^b: Follicular phase: 1.9–12.5 mIU/mL Midcycle: 8.7–76.3 mIU/mL Luteal phase: 0.5–16.9 mIU/mL Post-menopausal: 5.0–55.2 mIU/mL Pregnancy: <0.1–1.5 mIU/mL
	TSH	2.15 mIU/mL	Non-pregnant range: 0.40–4.50 mIU/mL Pregnancy ranges: First trimester: 0.26–2.66 mIU/mL Second trimester: 0.55–2.73 mIU/mL Third trimester: 0.43–2.91 mIU/mL
	TPO	0.0 IU/mL	0.0–8.9 IU/mL
	Hemoglobin A1c	5.3%	<5.7%
Year 2 Lab 1 (day 3 of menstrual cycle)	FSH	15 mIU/mL	FSH^a range as above
Year 2 Lab 1 (day 3 of menstrual cycle)	AMH	0.2 ng/mL	0.15–7.5 ng/mL^c
Year 2 Lab 2 (day 2 of menstrual cycle)	FSH	32.9 mIU/mL	FSH range as above^a
	LH	6.0 mIU/mL	LH range as above^b
	Prolactin	8.9 ng/mL	Non-pregnant: 3.0–30.0 ng/mL Pregnant:10.0–209.0 ng/mL Postmenopausal: 2.0–20.0 ng/mL
Year 2 Lab 3	FSH	17.9 mIU/mL	FSH range as above^a
	LH	5.7 mIU/mL	LH range as above^b
	Estradiol	<15 pg/mL	Normal menstruation^d: Follicular phase: 12.5–166.0 pg/mL Ovulation phase: 85.8–498.0 pg/mL Luteal phase: 43.8–211.0 pg/mL Post-menopausal: 5.0–54.7 pg/mL Pregnancy (first trimester): 215–4300 pg/mL
	Total testosterone	13 ng/mL	2–45 ng/mL
	Progesterone	0.6 ng/mL	Normal menstruation: Follicular phase: <1.0 ng/mL Luteal phase: 2.6–21.5 ng/mL Post-menopausal: <0.5 pg/mL Pregnancy ranges: First trimester: 4.1–34.0 ng/mL Second trimester: 24.0–76.0 ng/mL Third trimester: 52.0–320 ng/mL
	AMH	0.01 ng/mL	AMH range as above^c
	ANA titer	1:80	<1:40 Negative 1:40–1:80 Low antibody level >1:80 Elevated antibody level
	CRP	0.5 mg/L	<8.0 mg/L
Year 2 Lab 4	Estradiol	65 pg/mL	Estradiol range as above^d
Year 2 Lab 5	AMH	<0.03 ng/mL	AMH range as above^c

FSH: follicle-stimulating hormone; LH: luteinizing hormone; TSH: thyroid-stimulating hormone; TPO: thyroid peroxidase; AMH: anti-Müllerian hormone; ANA: antinuclear antibody; CRP: C-reactive protein.

Labs are presumed to be collected at a random time in the menstrual cycle unless specifically indicated.

She was referred to a second gynecologist, where a repeat pelvic ultrasound showed a 4 mm polyp in the endocervical canal and two sub-serosal leiomyomas in the uterine fundus. She did not exhibit classic symptoms of polycystic ovary syndrome or hypogonadotropic hypogonadism. The gynecologist was concerned that her low AMH level, combined with her high FSH, could indicate perimenopausal changes with increased spacing between her menstrual cycles. Hysteroscopy for endocervical polyps was performed. The biopsy report showed benign proliferative-type endometrium with exogenous hormone effect.

She was then seen by a fertility specialist, who reported markedly diminished ovarian reserve and deemed her perimenopausal. She was informed that oocyte cryopreservation would be difficult due to low egg numbers and poor egg quality. Concerns arose regarding possible autoimmunity when her AMH level declined from 0.2 to <0.03, in conjunction with a borderline antinuclear antibody (ANA) titer of 1:80 and a strong family history of autoimmune diseases. However, two repeat ANA tests were negative, and she had a negative 21β-hydroxylase antibody. Additionally, genetic testing showed a normal 46, XX karyotype and negative fragile X test.

She underwent further evaluation by a rheumatologist, where no evidence of an ongoing systemic autoimmune or rheumatological disorder was found. However, the rheumatologist indicated some patients with an autoimmune predisposition or family history may exhibit stronger immune reactions to infections or other stimuli, though it remained unclear whether this could play a role.

Of note, she continued to have a firm, mobile, subcutaneous cystic mass on her left arm 2 years after the COVID-19 vaccination. Ultrasound revealed a lymph node at the site of palpable abnormality, likely reactive in etiology. Subsequent biopsy confirmed benign fibrosis at the area of concern.

She is currently undergoing periodic egg retrieval with a second fertility specialist, which has been challenging.

Patient perspective

“In October 2022, ~3 months after a COVID-19 infection and approximately coinciding with one full folliculogenesis cycle, I experienced the sudden onset of extreme menstrual irregularities. My only prior cycle disruption had occurred following the second dose of the Pfizer-BioNTech vaccine in April 2021, which caused a double cycle within 1 month but resolved quickly. After the COVID infection, my cycles became increasingly erratic, marked by significant changes in frequency, duration, volume, and consistency. With no prior history of menstrual irregularities, I became concerned by the apparent association between these cycle irregularities and both the COVID-19 infection and vaccination, as well as the later emergence of additional unexplained symptoms, including pityriasis rosea, cyst formation, and transient inflammation at the vaccine injection site, and slightly but persistently elevated ANA levels. With all symptoms not presenting at once, my primary care provider pursued general reproductive health assessments and referred me to an OB/GYN, who initially ruled out premature menopause and noted a temporary elevation in white blood cell count. I was offered either birth control or a hysterectomy to regulate cycles, neither of which addressed the underlying issue or explained the sudden onset of symptoms. It was only after explicitly stating my desire for biological children I was referred to a reproductive endocrinologist (RE), marking the beginning of a lengthy, costly, and at times frustrating diagnostic journey—not due to the complexity of my case, but due to how frequently providers dismissed my observations and concerns about a possible COVID-related issue. Different REs attributed my symptoms to premature menopause, endometriosis, exposure to microplastics, and genetic factors a priori, without testing to substantiate hypotheses.

Five months after the onset of symptoms, I was diagnosed with diminished ovarian reserve based on AMH, FSH, and Antral Follicles Count tests and was told conception with my own eggs was unlikely. I was advised to consider adoption or an egg donor. It took additional consultations and persistent self-advocacy to receive any follow-up testing and eventually a diagnosis of premature ovarian insufficiency (POI). My clinical presentation has deviated somewhat from classic POI, as I continue to show signs of transient ovarian function. My AMH, for example, has fluctuated atypically, dropping from 0.20 to 0.01 but later rebounding to 0.18 ng/mL, suggesting a dynamic rather than a monotonic decline in ovarian function. My ovarian biomarkers have varied significantly since diagnosis, but my response to stimulation has remained relatively constant with different in vitro fertilization protocols, including antagonist and duostim protocols as well as investigational treatments like platelet-rich plasma injections in the ovaries. Since October 2023, I have undergone four controlled ovarian hyperstimulation cycles, each resulting in the retrieval of a single egg. The first was cryopreserved, the second was not viable due to a fractured zona, the third was fertilized and preserved as a good-quality embryo for future transfer, and the fourth was recently retrieved and fertilized, with the outcome pending. Despite three to four follicles resent in each cycle, they do not grow in a synchronized manner. Given that I continue to produce follicles, it seems premature to conclude that conception using my own eggs is ‘impossible’, although I do recognize the very low probability of a live birth given my ‘poor responder’ status. We have missed several opportunities to collect and analyze follicular fluid during retrievals and at the onset of symptoms, which could have improved our understanding of the potential link between my ovarian dysfunction and COVID-19 or another cause. The lack of provider engagement with possible immune-mediated mechanisms of ovarian failure has been deeply frustrating, particularly given my persistent ANA elevation, cyst formation and inflammatory reactions at the vaccine site, and the absence of genetic or karyotype causes for failure and no classic evidence of endometriosis-related failure like pain. My case underscores the urgent need for more research into the long-term reproductive effects of COVID-19 and its vaccines, as well as the role of immune dysregulation. Given the number of anecdotal cases of post-COVID or post-vaccine menstrual irregularities and growing number of experiences within my own peer group that remain undocumented, it is imperative that the medical community considers emerging data and patient observations, rather than prematurely attributing cycle disruptions to conventional causes without thorough investigation.”

Discussion

This is a unique case of COVID-19-induced AUB in a nulligravid patient with a strong family history of autoimmune diseases. Although she did not fully meet the ESHRE criteria for POI with only one FSH level >25 mIU/mL, this was thought to be the most likely diagnosis. Prior published case reports have described POI after COVID-19, characterized by a rise in FSH levels and infertility.^5,16 Initial clinical and cell-based research has shown that COVID-19 may influence the human reproductive system,^15,17–20 with evidence of reproductive endocrine disorders and declining ovarian reserve.⁵ SARS-CoV-2, the causative virus of COVID-19, enters cells through the surface angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2. Notably, cells of the endometrium and ovary also express ACE2, raising the possibility that direct SARS-CoV-2 invasion could impact reproductive function in females with COVID-19.^5,17–19

Other contributing factors may include excessive immune or inflammatory responses following viral infection, leading to complement cascades, chemotaxis, cytokine release, and phagocytosis or apoptosis of infected cells.^5,16 These immune responses could disrupt the hypothalamic-pituitary-ovarian axis and steroidogenesis.⁵ A 2021 study showed that women affected by COVID-19 had significantly lower serum AMH levels and higher testosterone and progesterone levels than age-matched, healthy unaffected women, suggesting a poor ovarian reserve and abnormal reproductive hormones.⁵ Other studies have reported altered LH, FSH, estradiol, prolactin, and AMH levels in women recovering from COVID-19, supporting the hypothesis of virus-induced ovarian dysfunction²⁰ (Table 2).

Table 2.

Summary of cases of ovarian dysfunction associated with COVID-19.

Publication	Summary	Points to highlight
Puca and Puca³	27-year-old presenting with amenorrhea, after COVID-19. She was found to have high FSH, low estrogen and low AMH. She started OCPs and menstrual cycles returned	Case of amenorrhea as a post-COVID-19 complication
Ding et al.⁵	Observational study of 78 women with COVID-19 were compared with that of age-matched healthy women. Women with COVID-19 had lower serum AMH, higher testosterone, and prolactin	Study showing differences in hormone levels in healthy versus COVID-19 infected women
Madaan et al.¹⁵	34-year-old female presenting with irregular menses and infertility after COVID-19 found to have low AMH and high CRP. She was treated with assisted reproductive technology	Case of infertility after COVID-19 with evidence of abnormal labs
Wilkins and Al-Inizi¹⁶	34-year-old presenting with infertility. Initial lab work with normal FSH and LH and regular menstrual cycles; however, after COVID-19, she had elevated FSH and LH and low progesterone	Case demonstrating changes in FSH and LH before and after COVID-19
Stern et al.²⁵	35-year-old with history of infertility and failed intrauterine insemination had worsening lab work after COVID-19. After failing IVF, she was suspected to have autoimmune ovarian insufficiency and treated with prednisone. She was able to have a successful pregnancy	Case highlights suspected autoimmune ovarian insufficiency after COVID-19 with steroid treatment
	28-year-old who had successful IVF prior to the pandemic had failed IVF after COVID-19 diagnosis. Given prior success with administering steroids for COVID-19 antibody-associated poor ovarian response, she was given prednisone and achieved pregnancy (however, later had miscarriage)	Case of steroid treatment after COVID-19 resulting in pregnancy
	35-year-old female with infertility was found to have positive COVID-19 nucleocapsid antibody. She responded to high dose letrozole and conceived and delivered twins	Case of infertility in the setting of COVID-19 antibodies

AMH: anti-Müllerian hormone; COVID-19, coronavirus disease 2019; CRP: C-reactive protein; FSH: follicle-stimulating hormone; IVF, in vitro fertilization; LH: luteinizing hormone; OCPs: oral contraceptive pills.

A well-documented connection exists between viral infections and autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, celiac disease, and multiple sclerosis.²¹ Viruses known to play a role in autoimmune diseases include hepatitis C virus and hepatitis B virus. More recently, growing evidence indicates that SARS-CoV-2 is also associated with autoimmunity.²¹ The proposed underlying mechanisms between viruses and autoimmune diseases include molecular mimicry, bystander activation, and epitope spreading.^21–23 Molecular mimicry occurs when a pathogen expresses antigens structurally similar to host antigens, leading to autoreactive T cells attacking both the foreign pathogen and host cells.^21,22 Bystander activation involves the nonspecific activation of T cells during an immune response, which may activate autoreactive T cells that recognize self-antigens.^21–23 Epitope spreading occurs when an immune response initially directed to a specific antigen epitope broadens to target more epitopes on the same or different antigens.²⁴ Individuals susceptible to developing these autoimmune reactions may be more likely to experience pathogenic effects from infections or even vaccine components.²² A 2021 literature review summarized the presence of multiple autoantibodies in patients with COVID-19, including ANA, anti-Ro/SSA, rheumatoid factor, and lupus anticoagulant.²¹ The most frequent COVID-19-associated autoimmune conditions were vasculitis and arthritis.²¹

There are also documented cases of autoimmune POI after COVID-19.^25,26 Autoimmune POI is categorized into adrenal or non-adrenal autoimmunity, which may present as localized or systemic disorders.²⁶ Of the 1%–4% of women diagnosed with POI, 5% are believed to have an autoimmune etiology, with 60%–80% of those involving adrenal autoimmunity.^7,26

Interestingly, 10%–30% of women with POI have a concomitant autoimmune disease, with autoimmune thyroiditis and diabetes mellites type 1 being most common.^11,26 Diagnostic criteria for autoimmune POI are not well defined, but proposed criteria include the presence of autoantibodies (ovarian, adrenocortical, or steroidogenic), presence of an autoimmune disease, and/or ovarian biopsy showing lymphocytic infiltration.²⁶

There are numerous antibodies that have been considered as markers for autoimmune POI including anti-oocyte antibodies (AOAs), steroid-producing cell antibodies (StCA), and adrenocortical antibodies (ACA). AOAs include a wide range of targets including the FSH β-subunit, corpus luteum, zona pellucida, granulosa cells, anti-α-enolase, aldehyde dehydrogenase-1A1, and selenium binding protein 1.^11,27 StCA related to POI include 21OH, 17α-hydroxylase, and cytochrome P450 side-chain cleavage.^11,27 Anticardiolipin or ANAs may also play a role. The ESHRE guidelines restrict the autoimmune work-up to ACA or 21OH and thyroid TPO antibodies.²⁷ Ovarian biopsy can be helpful at detecting autoimmune ovarian destruction, but this can affect ovarian reserve and would need caution if patients are undergoing fertility work-up.²⁷ One study showed that total inhibin levels were helpful at differentiating autoimmune and idiopathic POI, with autoimmune POI having significantly higher serum values.²⁸ Diagnosis of autoimmune POI remains challenging and relies on several clinical, immunological, and histological features that should be investigated in patients suspected to have this condition.²⁷

This patient had borderline ANA values and a strong family history of autoimmune diseases, which may have led to an exaggerated immune reaction to SARS-CoV-2 infection. She also experienced a brief menstrual irregularity following COVID-19 vaccination and localized arm in-flammation, further supporting her tendency to exhibit heightened immune reactions. Although 21-hydroxlase antibody was negative, consideration for other antibody tests or inhibin levels to determine whether she was having an autoimmune etiology may have helped to explain her AUB and fertility concerns. An ovarian biopsy can also provide information for a diagnosis; however, the patient was undergoing fertility treatments, and therefore, biopsy would not be recommended.

Currently, guidelines are insufficient for autoimmune POI treatments. The evidence on steroid or immunosuppressive therapy remains controversial. Typically, the treatment follows the same approach for non-autoimmune POI, including hormone therapy and fertility interventions. Early recognition and treatment are important to minimize long-term complications.

Conclusion

This case highlights the potential long-term effects of COVID-19 on the female reproductive system leading to AUB and infertility. It is important to note that COVID-19 has also been associated with the development of autoimmune conditions, including autoimmune POI, and is important to keep on the differential diagnosis for patients experiencing menstrual cycle changes after a viral illness and a strong family or personal and history of autoimmune conditions. The diagnostic criteria for autoimmune POI continue to be investigated, and medical providers are encouraged to conduct a thorough work-up including antibody testing when this diagnosis is being considered.

Footnotes

Acknowledgements

The authors acknowledge Ellen Aaronson, MS, AHIP, Mayo Clinic Libraries, who is an important member of Mayo Clinic and provided an extensive literature search for this manuscript.

ORCID iDs

Adrianna Clapp

Ridwan Ahmad

Bala Munipalli

Ethical Considerations

Our institution does not require ethics approval for reporting individual cases or case series.

Consent for Publication

Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.

Author Contributions

All authors (1) made a significant contribution to the concept, design, acquisition, analysis, or interpretation of data; (2) drafted the article or revised it critically for important intellectual content; (3) approved the final version of the article for publication; and (4) agreed to be accountable for all aspects of the work and resolved any issues related to its accuracy or integrity.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data supporting this case report are derived from the patient’s electronic medical records and are available from the corresponding author upon reasonable request, subject to ethical and privacy considerations.

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