<div>Premature ovarian insufficiency</div><div>secondary to COVID-19 infection: an original case report</div><div>Shortened title: COVID-19 induced premature ovarian insufficiency</div><div>Dr James Wilkins<sup>1</sup></div><div>Email address:
james.wilkins2@nhs.net</div><div><div>Telephone: +447564 977847</div></div><div>Address: Department of Obstetrics and Gynaecology</div><div>South Tyneside &amp; Sunderland Royal Hospital</div><div>South Shields</div><div><div>NE34 0PL


United Kingdom</div></div><div>Dr Shamma Al-Inizi<sup>2</sup></div><div>Email address:
shamma.al-inizi@stft.nhs.uk</div><div><div>Telephone: +447821 708743</div></div><div>Address: Department of Obstetrics and Gynaecology</div><div>South Tyneside &amp; Sunderland Royal Hospital</div><div>South Shields</div><div><div>NE34 0PL


United Kingdom</div></div><div>1 Foundation doctor in the department of Obstetrics and Gynaecology,
South Tyneside &amp; Sunderland NHS Foundation Trust, United Kingdom</div><div>2 Consultant Obstetrician and Gynaecologist, Department of Obstetrics
and Gynaecology, South Tyneside &amp; Sunderland NHS Foundation Trust,
United Kingdom</div><div>Main Document</div><div>Background:</div><div>In late December 2019, several patients began to develop signs and
symptoms consistent with a viral pneumonia in Wuhan, China. This disease
spread, becoming a global pandemic and was eventually identified to be a
novel strain of coronavirus termed coronavirus disease 2019 (COVID-19).
A significant proportion of patients infected with this virus
unfortunately develop severe disease associated with acute respiratory
distress syndrome, hypercoagulability and neurological disease amongst
other complications(1) and, as of the 16/2/21, there have been 108.7
million cases and 2.4 million reported deaths globally(2). There is
increasing recognition that a proportion of patients who contract this
acute infection will develop a subsequent long-term illness. The range
of symptoms attributed to this is large but most commonly include
fatigue, shortness of breath and myalgia(3). This long-term illness is
thought to be secondary to chronic tissue inflammation. There is a risk
that reproductive tissue may also be vulnerable, potentially resulting
in subfertility, but to date no cases of deranged ovarian function
secondary to COVID-19 have been reported.</div><div>Case report:</div><div>A 34-year-old lady presented to the fertility clinic at South Tyneside
District Hospital in November 2020 with primary subfertility after
having regular unprotected sexual intercourse for over one year. She and
her partner were investigated for this; a hysterosalpingogram
demonstrated patent fallopian tubes and her partner’s seminal fluid
analysis was normal. Ovarian function was investigated with blood tests.
These demonstrated high gonadotrophin levels and a very low progesterone
level of 0.3nmol/L consistent with premature ovarian insufficiency
(POI). The common causes of this were investigated but none were
identified, nor did she have a positive family history of POI.
Polycystic ovarian syndrome was excluded due to a normal transvaginal
ultrasound scan and lack of clinical and biochemical evidence of
hyperandrogenism. She was a non-smoker with a healthy BMI, had had
neither pelvic surgery nor chemo/radiotherapy previously. In terms of
comorbidities, she was fit and well other than well controlled
hypothyroidism, which was medicated with levothyroxine with a recent TSH
of 0.98mUI/L, in the normal range.</div><div>Interestingly, this lady was diagnosed with COVID-19 in April 2020 by a
nasopharyngeal swab demonstrating positive viral serology. During the
acute illness she developed symptoms of shortness of breath, fatigue,
myalgia and headache but did not require hospitalisation nor active
treatment for these symptoms. Her shortness of breath improved over the
course of two to three weeks but she experienced persistent fatigue and
continuing myalgia over the next few months. She has been referred to
the long COVID clinic due to this. In addition, her periods became
irregular with oligomenorrhoea and she began to experience regular hot
flushes and night sweats. Two months prior to contracting COVID-19, in
February 2020, she was referred to the fertility clinic and at this time
she had normal regular periods and normal gonadotrophin levels: FSH 8U/L
and LH 2U/L. However in November 2020, seven months after her acute
infection, her FSH was 78U/L and LH 43U/L and on repeat two months later
her gonadotrophins were persistently raised: FSH 89U/L and LH 32U/L.</div><div>These events mean that this lady is very unlikely to fall pregnant
without support and one of the available options is trying to conceive
via assisted reproduction with egg donation or adoption, hence a
referral to the local IVF centre was arranged.</div><div>Due to the novel nature of this presentation, written consent to publish
this case was obtained from the patient.</div><div>Discussion:</div><div>It is well established that viruses can cause inflammation of
reproductive tissue; indeed one of the most common clinical
manifestations of mumps is orchitis, which can be damaging to testicular
function. Further, several case reports have discussed the development
of orchitis in patients who have contracted COVID-19 and small studies
have shown pathological changes to testicular tissue in some affected
with this virus(4). A possible mechanism for this is expressed in Figure
1. Reproductive tissue expresses the ACE2 receptor and COVID-19 may
utilise this to gain cellular entry(5, 6). Viral entry to these cells
would promote an inflammatory response through the complement cascade
and associated chemotaxis, phagocytosis of virally infected cells and
presentation of this antigen causing local T cell activation and
cytokine release by a myriad of immunological cells(7). These effects
have the potential to cause significant cellular demise either directly
through apoptosis and phagocytosis or indirectly through mechanisms such
as the disruption of tissue microvasculature(7). These could cause
sufficient damage to impair steroidogenesis and ovulation affecting
fertility.</div><div>Despite this mechanism and positive histological findings in males, to
date these studies have not found these microscopic changes in ovarian
tissue following infection with COVID-19 nor have there been case
reports describing an effect of COVID-19 on female sex hormones or
fertility. This may be due to several factors. Firstly, the ACE2
receptor is less expressed in ovarian tissue compared to testicular
tissue(8) meaning the change of viral invasion to this tissue and
subsequent damage may be less. Another explanation may be that there
have been very few studies examining ovarian tissue histologically
following COVID-19. This means it is very possible an effect of COVID-19
on this tissue may have thus far gone undetected. In addition,
investigation of subfertility is normally only undertaken following a
minimum of one year of regular unprotected sex. As the pandemic began to
spread worldwide in early 2020, it is likely that if COVID-19 were to
impact on the ovarian function of a significant proportion of women then
the impact of this would not be investigated until early 2021 and
therefore would not begin to be apparent until this time.</div><div>The COVID-19 pandemic is the largest health challenge the world has
faced in modern times with many people already having been infected by
this virus. The possibility that a cohort of women may have contracted
thus far undiagnosed COVID-19-induced subfertility with more at risk of
developing this, means that health professionals working in fertility
should be highly alert to this potentiality and more work should be
performed to investigate this further. If more evidence is gathered
consistent with this hypothesis, then a lower threshold for treatment
aiming to reduce inflammation to protect ovarian function should be
considered and women should be made aware of this risk.</div><div>Word count: 1025 words.</div><div>Declarations</div><div>We have no conflicts of interest related to this publication to declare
and there has been no financial support for this work. The finished
publication has been reviewed and approved for submission by all
corresponding authors. Written consent for this case report has been
obtained from the patient and as this work is a case report formal
ethical approval was not required.</div><div>Contribution to authorship</div><div>Primary Author: Dr James Wilkins (JW)</div><div>JW assessed the patient about whom this case report is detailed in
clinic alongside SAI and, following this, planned this case report,
assessed the background literature and hypothesised a potential
mechanism for the association described. Following this, JW wrote up
this work with contributions from SAI.</div><div>Secondary Author: Dr Shamma Al-Inizi (SAI)</div><div>SAI was the primary assessor of this lady in her subfertility clinic and
suggested the case would merit publication, encouraging JW with this.
SAI then reviewed the work produced by JW making changes and suggestions
as appropriate in the writing up process before giving her approval for
submission.</div><div>Figures:</div><div>Figure 1: Possible mechanism of COVID-19 induced premature ovarian
insufficiency</div><div>References:</div><div>1. Public Health England. COVID-19: epidemiology, virology and clinical
features. 2021.</div><div>2. World Health Organisation. Coronavirus disease (COVID-19) pandemic,
Available at: .</div><div>3. Iacobucci G. Long covid: Damage to multiple organs presents in young,
low risk patients. BMJ. 2020;371:m4470.</div><div>4. Madjunkov M, Dviri M, Librach C. A comprehensive review of the impact
of COVID-19 on human reproductive biology, assisted reproduction care
and pregnancy: a Canadian perspective. Journal of Ovarian Research.
2020;13(1):140.</div><div>5. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T,
Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and
Is Blocked by a Clinically Proven Protease Inhibitor. Cell.
2020;181(2):271-80.e8.</div><div>6. Henarejos-Castillo I, Sebastian-Leon P, Devesa-Peiro A, Pellicer A,
Diaz-Gimeno P. SARS-CoV-2 infection risk assessment in the endometrium:
viral infection-related gene expression across the menstrual cycle.
Fertil Steril. 2020;114(2):223-32.</div><div>7. Murphy K, Weaver C. Janeway’s Immunobiology. 9 ed: W. W. Norton &amp;
Company; 2017 2017. 928 p.</div><div>8. Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, Lindskog C. The
protein expression profile of ACE2 in human tissues. Molecular Systems
Biology. 2020;16(7):e9610.</div>