Key Points in Fertility Preservation Treatment Strategies during COVID-19 Pandemic. An Update on Pharmacological Therapies

Abstract

The fertility preservation (FP) field has developed in the two decades and offers women the possibility to have genetic children at some point in life. Fertility preservation is urgent by definition, performed for social reasons or medical indications, such as impending gonadotoxic therapy or radical gynaecological surgery. One year after the pandemic was
declared, the COVID-19 infection imposed several restrictions and limited access to health care for the infertile couple. Ovarian stimulation is a pharmacological treatment used to induce the development of ovarian follicles; FP guidelines provide different options for ovarian stimulation. We performed a systematic search on fertility preservation (FP) procedures during the COVID-19 pandemic using the keywords: FP, ovarian stimulation, assisted reproduction techniques (ART), and COVID-19. In order to update the different treatment strategies in ovarian stimulation on fertility preservation studied in the last ten years, we searched for randomized clinical trials (RCTs) focused on therapeutic agents used in current protocols, gonadotropins, gonadotropin releasing hormone (GnRH), clomiphene citrate (CC), letrozole, androgens, metformin, tamoxifen, glucocorticoids, aspirin, coenzyme Q10, and sildenafil. Fertility may be influenced by SARS-CoV-2 infection - especially in
men; until more evidence confirms the effects on fertility, patients with COVID-19 positive should delay FP procedures if possible. Access to fertility conservation services decreased during the analysed period due to the medical services restrictions and the reorientation of medical resources on patients with COVID-19, without major changes in the current therapeutic protocols. In terms of pharmacotherapy in ovarian stimulation (OS) procedures, letrozole is first line therapy, superior to CC for OS. Similar ovulation and pregnancy rate can be obtained in letrozole - induced ovulation compared to gonadotropin protocol. Adjuvant therapies may be used for OS but lack proven efficacy. Further studies on adjuvant therapies and complementary support are needed, to ensure optimal condition in assisted reproductive interventions for fertility preservation, especially in gonadotoxic therapies.

Full text

FARMACIA, 2021, Vol. 69, 2
189
https://doi.org/10.31925/farmacia.2021.2.1
REVIEW
KEY POINTS IN FERTILITY PRESERVATION TREATMENT
STRATEGIES DURING COVID-19 PANDEMIC. AN UPDATE ON
PHARMACOLOGICAL THERAPIES
VALENTIN NICOLAE VARLAS 1,2, ROXANA GEORGIANA BORȘ 1, BOGDANA ADRIANA
NĂSUI 3*, MAGDALENA MITITELU 4, ALFRED REDALF ALEN GHEORGHIU 5, ANCA LUCIA
POP 4
1Department of Obstetrics and Gynaecology, “Filantropia” Clinical Hospital, 11 Ion Mihalache Boulevard, 011132,
Bucharest, Romania
2Department of Obstetrics and Gynaecology, “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu
Street, 020021, Bucharest, Romania
3Department of Community Health, “Iuliu Hațieganu” University of Medicine and Pharmacy, 6 Louis Pasteur Street,
400349, Cluj-Napoca, Romania
4Department of Clinical Laboratory, Food Safety, “Carol Davila” University of Medicine and Pharmacy, 6 Traian Vuia
Street, 020956, Bucharest, Romania
5Faculty of Medicine, “Transilvania” University, 56 Nicolae Bălcescu Street, 500019, Brașov, Romania
*corresponding author: adriana.nasui@umfcluj.ro Manuscript received: February 2021
Abstract
The fertility preservation (FP) field has developed in the two decades and offers women the possibility to have genetic
children at some point in life. Fertility preservation is urgent by definition, performed for social reasons or medical
indications, such as impending gonadotoxic therapy or radical gynaecological surgery. One year after the pandemic was
declared, the COVID-19 infection imposed several restrictions and limited access to health care for the infertile couple.
Ovarian stimulation is a pharmacological treatment used to induce the development of ovarian follicles; FP guidelines
provide different options for ovarian stimulation. We performed a systematic search on fertility preservation (FP) procedures
during the COVID-19 pandemic using the keywords: FP, ovarian stimulation, assisted reproduction techniques (ART), and
COVID-19. In order to update the different treatment strategies in ovarian stimulation on fertility preservation studied in the
last ten years, we searched for randomized clinical trials (RCTs) focused on therapeutic agents used in current protocols,
gonadotropins, gonadotropin releasing hormone (GnRH), clomiphene citrate (CC), letrozole, androgens, metformin, tamoxifen,
glucocorticoids, aspirin, coenzyme Q10, and sildenafil. Fertility may be influenced by SARS-CoV-2 infection - especially in
men; until more evidence confirms the effects on fertility, patients with COVID-19 positive should delay FP procedures if
possible. Access to fertility conservation services decreased during the analysed period due to the medical services restrictions
and the reorientation of medical resources on patients with COVID-19, without major changes in the current therapeutic
protocols. In terms of pharmacotherapy in ovarian stimulation (OS) procedures, letrozole is first line therapy, superior to CC
for OS. Similar ovulation and pregnancy rate can be obtained in letrozole - induced ovulation compared to gonadotropin
protocol. Adjuvant therapies may be used for OS but lack proven efficacy. Further studies on adjuvant therapies and
complementary support are needed, to ensure optimal condition in assisted reproductive interventions for fertility
preservation, especially in gonadotoxic therapies.
Rezumat
Domeniul conservării fertilității (FP) s-a dezvoltat în cele două decenii și oferă femeilor posibilitatea de a avea copii genetici
la un moment dat în viață. Conservarea fertilității este urgentă prin definiție, efectuată din motive sociale sau indicații
medicale, cum ar fi terapia gonadotoxică iminentă sau chirurgia ginecologică radicală. La un an de la declararea pandemiei,
infecția COVID-19 a impus mai multe restricții și a limitat accesul la îngrijirea sănătății pentru cuplul infertil. Stimularea
ovariană este un tratament farmacologic utilizat pentru a induce dezvoltarea foliculilor ovarieni; ghidurile FP oferă diferite
opțiuni pentru stimularea ovariană. Am efectuat o căutare sistematică a procedurilor de conservare a fertilității (FP) în timpul
pandemiei COVID-19 folosind cuvintele cheie: FP, stimulare ovariană, tehnici de reproducere asistată (ART) și COVID-19.
Pentru a actualiza diferitele strategii de tratament în stimularea ovariană privind conservarea fertilității studiate în ultimii zece
ani, am căutat studii clinice randomizate (RCT) axate pe agenții terapeutici utilizați în protocoalele actuale, gonadotropine,
hormonul eliberator al gonadotropinei (GnRH), citrat de clomifen (CC), letrozol, androgeni, metformină, tamoxifen, gluco-
corticoizi, aspirină, coenzima Q10 și sildenafil. Fertilitatea poate fi influențată de infecția cu SARS-CoV-2 - în special la bărbați;
până când mai multe dovezi confirmă efectele asupra fertilității, pacienții cu COVID-19 pozitiv ar trebui să amâne procedurile
FP dacă este posibil. Accesul la serviciile de conservare a fertilității a scăzut în perioada analizată din cauza restricțiilor
serviciilor medicale și a reorientării resurselor medicale către pacienții cu COVID-19, fără modificări majore în protocoalele
terapeutice actuale. În ceea ce privește farmacoterapia în procedurile de stimulare ovariană (OS), letrozolul este terapia de

FARMACIA, 2021, Vol. 69, 2
190
primă linie, superior clomifenului (CC) în OS. O ovulație și o rată de sarcină similară pot fi obținute în ovulația indusă de
letrozol în comparație cu protocolul gonadotropinei. Terapiile adjuvante pot fi utilizate pentru OS, dar nu au o eficacitate
dovedită. Sunt necesare studii suplimentare privind terapiile adjuvante și sprijinul complementar, pentru a asigura o stare
optimă în intervențiile de reproducere asistată pentru conservarea fertilității, în special în terapiile gonadotoxice.
Keywords: fertility preservation, ovarian stimulation, pharmacological agents, assisted reproductive techniques, COVID-19
Introduction
The COVID-19 pandemic has brought a series of
significant changes in all areas of activity and continues
to weaken health systems around the world [1-3].
Fertility societies responded to the pandemic with the
abrupt cessation of clinical interventions and the closure
of fertility clinics, with some exceptions in the case
of urgent conservation of fertility, a decision with a
significant psychosocial impact on patients [4].
The global in vitro fertility (IVF) market was affected
by the various restrictions of 2020, but it is still expected
to recover and grow with a compound annual growth
rate (CAGR) of 12% by 2023 [4], reflecting the increased
number of people tuning into their reproductive health
in recent years. Most of the time, infertility is a time-
sensitive issue, if not from a medical but psychological
perspective.
Cancer itself, gonadotoxic treatment, surgical procedures
for benign or malignant gynaecological affections may
determine gonadal damage and diminished ovarian
reserve [5, 6]. Cytotoxic and immunomodulatory agents
have a broad spectrum of undesired effects, on different
organs and tissues, including the reproductive system
[6-8], which may cause premature ovarian insufficiency
(POI), infertility, and early menopause. Major factors
determining the risk of induced POI are the type of
agent, the dose, and the length of chemotherapy
exposure. The patient’s age at the moment of treatment
is noticed to be a related factor for POI [9]. Less is
known about the impact of the SARS-CoV-2 pandemic
on fertility care.
Our study's objectives are to systematically evaluate
the influence of the SARS-CoV-2 infection on fertility
care from the beginning to the present moment, with
an update of the scientific data on pharmacotherapy
agents used for fertility preservation (FP's) ovarian
stimulation protocols in the last ten years.
Materials and Methods. Data Search
The first purpose was to perform a systematic search
to the Preferred Reporting Items for Systematic Review
and Meta-Analysis (PRISMA) guidelines on original
published papers on topics (1) “fertility preservation”,
(2) “ovarian stimulation” and (3) “assisted reproductive
techniques” – with a data filter on (AND) “COVID-
19” – published in scholarly peer-reviewed journals
(with no country restriction) during the pandemic
period (the year 2020 - present) (Figure 1). The
analysis on the last ten years refined to RCT/CT
observed the constant interest at a low level on fertility
preservation topic, and an alarming decrease in assisted
reproductive techniques (ART) in 2020 (Figure 2).
The present study's next purpose was to systematically
review and evaluate the role of different therapeutic
strategies on pregnancy achievement. Clinical trials
(CT), meta-analyses (MA), and randomized controlled
trials (RCTs) that evaluated eleven therapeutic agents
(gonadotropins, GnRH, clomiphene citrate, letrozole,
androgens, metformin, tamoxifen, glucocorticoids,
aspirin, coenzyme Q10 and sildenafil) were included.
Relevant studies published in the English language
were comprehensively selected using PubMed/Medline
and WoS until 2021. We included studies among ten
years periods that investigated various agents during
IVF protocol and reported pregnancy outcomes
(Figures 1, 2, 3 and 4).
Study selection
PubMed®/MEDLINE data search. Association “COVID-
19” and “fertility preservation”, revealed three results;
the search refined to randomized controlled trials,
clinical trials (RCT/CT) or reviews, systematic reviews
or meta-analysis (R/SR/MA) retrieved no results;
“COVID-19” and “assisted reproductive techniques”
retrieved seven results, “COVID-19” and “ovarian
stimulation” retrieved no results.
Web of Science data search. For the association
“COVID-19” and “fertility preservation”, the search
retrieved three results; “COVID-19” and “assisted
reproductive techniques” retrieved three results,
“COVID-19” and “ovarian stimulation” retrieved four
results. Bargraph of data retrieved on fertility preservation
on period 2020 to present is described in Figure 1.
Over 88 studies were identified and screened for
eligibility; according to the topic search, data extracted
included demographic variables, participants in the
study, treatment and safety profile. Thirty five papers
were included in the present study section, cantered
on the main topics included in the search.
A total of 4071 studies were published on “ovarian
stimulation” and “pharmaceutical agents” (letrozole,
human chorionic gonadotrophin, gonadotropin-releasing
hormone antagonist and agonist, recombinant FSH,
human menopausal gonadotropin, glucocorticoids,
androgens, aspirin, metformin, clomiphene citrate,
coenzyme Q10, and sildenafil) on the PubMed®/
Medline and Web of Science databases, from the past
ten years, with 650 randomized controlled trials. In
the last year, we observed and analysed thirty-nine
RCT on ovarian stimulation (OS) therapies in ART.

FARMACIA, 2021, Vol. 69, 2
191
Figure 1.
Chart of a systematic search for the keywords “fertility preservation” and “ART” on the PubMed® database
refined to RCT/CT (ten years topic: 2010 - 2020)
Figure 2.
Bargraph of data retrieved on Web of Science search on fertility preservation since 2020, on publication domain.
The search retrieved 918 studies (Obstetrics and Gynaecology, Oncology, Reproductive Biology, Genetics
Heredity, General Medicine)
Figure 3.
Distribution of research papers on pharmaceutical agents used in ovarian stimulation protocols - ten years topic
(2010 - 2020) (total randomized controlled trials/controlled trials-black, meta-analyses/systematic reviews –
grey, total papers on topic – light grey)

FARMACIA, 2021, Vol. 69, 2
192
Figure 4.
The systematic search for the keywords “ovarian stimulation” AND “gonadotropins”, “GnRH”, “clomiphene
citrate”, “letrozole”, “androgens”, “metformin”, “tamoxifen”, “glucocorticoids”, “aspirin”, “coenzyme Q10” and
“sildenafil” on the PubMed® database refined to CT/MA/RCT (the pandemic COVID-19 period)
The statistical analysis was performed using Microsoft
Excel® 2013 (Microsoft® Corporation, Redmond,
WA, USA).
The current state of knowledge on SARS-CoV-2
and human reproduction
Genomic analysis reveals that the new SARS-CoV-2
respiratory virus entry into cells mediated by the viral
spike (S) protein via angiotensin-converting enzyme 2
(ACE2) receptors, enhanced by transmembrane serine
protease 2 (TMPRSS2) [10]. Afterwards, the viral RNA
is released, replication and transcription begin [11].
SARS-CoV-2 infection disrupts the renin-angiotensin
system by downregulating ACE2 expression in the cells
generating a pro-inflammatory response. Components
of the renin-angiotensin system, Ang (1-7), Ang II,
and ACE2, control essential reproductive system
functions [12].
COVID-19 on male fertility
Studies show that ACE2 receptors are more expressed
in the male reproductive system than in the female.
ACE2 in the testis is highly expressed, with high
levels in Leydig and Sertoli cells, and regulates the
testicular and sperm function [12, 13[.
SARS-CoV-2 can affect testicles through the genomic
similarity with SARS-CoV. The virus's binding to
ACE2-positive cells in testis could generate severe
alteration of testicular tissue eventually provide sites
for viral infection. The existing studies reveal only
the male reproductive system and function injury
regarding transmissibility so that the coronavirus
outbreak may have a serious impact on fertility
worldwide.
The SARS-CoV-2 infection affects male fertility by
acting on testicular tissue (Sertoli cells); thus, the
secretion of semen affects spermatogenesis; secretions
from the prostate are harmful. Subsequent studies
in recovered patients will analyse the effect of the
virus on orchitis determinism and the correlation with
spermatogenesis and infertility [14, 15]. Another
element is related to the associated diseases (cancer
patients) and the possible impact on the overall out-
come of SARS-CoV-2 infection, increasing the degree
of infertility [16].
COVID-19 and female fertility
The evidence available suggests that ACE2 is expressed
in the breasts, uterus, vagina, fallopian tube, placenta
and most abundantly in the ovary, with high oocyte
levels. The renin-angiotensin system's female reproductive
system components control follicle development,
steroidogenesis, oocyte maturation, ovulation, endometrial
regeneration and embryo development. The broad
expression of ACE2 in the female reproductive tract
COVID-19 may favour the infection and disturb the
female reproductive functions [12, 17].
Fertility preservation and ART during the COVID-
19 pandemic
Although recommendations from all relevant bodies
supported the non-interrupted access to emergency
fertility care even during lockdown periods [18, 19],
there were raised many concerns and uncertainties for
the oncofertility patients related to the full availability
of treatments under the pandemic state.
Other pandemic-generated aspects impacting the
fertility care sector are the following: the risk of
viral transmission to patients, their gametes, embryos
and reproductive tissues or the increased risk of assisted
reproduction cycle cancellation due to superimposed
infection with SARS-CoV-2. These issues are even
more stringent for patients living in - remote areas -
or developing countries [20].
COVID-19 and ART procedure have a coexisting issue
of thrombotic risk [21, 22]. ART procedures have a

FARMACIA, 2021, Vol. 69, 2
193
risk of thromboembolic complications in the case of
OHSS. In COVID-19 positive women, any risk of
OHSS should be avoided, and prophylactic measures
are mandatory [23].
Screening for SARS-CoV-2 in fertility preservation
programs
There is a narrow fertility window in oncological
patients to preserve their reproductive potential, so
an active infection while proceeding with FP treatment
could compromise the whole procedure and the
patient's reproductive potential. Besides, during the
entire routine of IVF procedure, the patient is exposed
to a potentially COVID-19 interference. Although
universal screening for COVID-19 is the ideal scenario
[24], in real life, the availability of testing resources
varies widely [25]. It is established that all patients
resorting to ART must be subjected to triage, but there
is no consensus yet on the optimal way of screening
triage-negative asymptomatic patients attending the
fertility clinic [26, 27].
Considering the disastrous consequences of an un-
detected SARS-CoV-2 infection in a fertility case,
screening the patient (and partner) at least at the
beginning of the FP treatment is mandatory [27].
The optimal screening algorithm remains unknown,
but ideally, both serology and molecular tests should
be used as the combined approach significantly increases
detection rates [28].
It is necessary to periodically test healthcare workers
from fertility clinics to avoid the nosocomial transmission
and risk of iatrogenic infection in the laboratory
samples.
Cryopreservation technique and its safety
Cryopreservation of embryos, reproductive cells and
tissues is a considerable part of any fertility program
and a technique with an exponential rise in assisted
reproduction usage for an expanding variety of
indications. So the question arose regarding the safety
of cryopreservation under the COVID-19 auspices.
Pomeroy et al., in a study published in 2010, reveal
the presence in the IVF laboratories of infectious
organisms and the negligible risks of transmission to
and between recipients. This information indicates
an insignificant probability of SARS-CoV-2 presence
in frozen reproductive specimens [29].
There is evidence that the risk of infectious cross-
contamination during cryopreservation and storage
is negligible [29] and the lack of cases of inflicting a
transmissible/communicable disease via laboratory
steps for IVF or cryopreservation is reassuring [30].
Data regarding the risk of virus transmission in gametes,
human embryos, and reproductive tissue by infected
people and the possibility of affecting early embryo-
genesis have many lacks [31]. Sperm, oocytes and
embryos are potential infectious disease sources,
including the SARS-CoV-2 virus [32].
The first study published by Baragann et al. about
viral RNA of SARS-CoV-2 detection in the oocytes of
women who were infected found that the viral RNA
was undetectable in all 16 oocytes studied, and there
will not be the vertical transmission of the virus [33].
Until September 2020, no studies were evaluating a
possible transmission of SARS-CoV-2 to oocytes in
infected women [31].
Cryopreservation protocols have been developed
individually for reproductive samples to minimize
cross-contamination and transmission risk, to guarantee
long-term safe storage and effective retrieval. When
repeated washing and cryopreservation protocols have
been respected, the samples' viral contamination risk
was very low in the IVF laboratory [32]. All of the
above and the fact that we are confronting a newly
emerged virus led to good laboratory and tissue practice
changes during the COVID-19.
Ovarian stimulation (OS) protocols
The first element in OS protocols consists of stimulation
with exogenous gonadotrophins to develop multiple
follicles, followed secondarily by the association of
gonadotropin-releasing hormone antagonist or agonist
(GnRH) to prevent premature ovulation. The third
element is represented by triggering the final maturation
36 - 38 hours before oocyte retrieval, commonly
with human chorionic gonadotrophin (HCG) or with
GnRH agonist in antagonist protocols.
In emergency fertility preservation, unconventional
protocols to facilitate the start of ovarian stimulation
have been proposed, such as immediate or random
start ovarian stimulation, luteal phase stimulation and
even double stimulation in the same menstrual cycle
(Follicular versus luteal phase ovarian stimulation
during the same menstrual cycle, DuoStim) [34]. These
protocols are typically at a lower risk of developing
the most feared iatrogenic complication of COS – the
ovarian hyper-stimulation syndrome (OHSS), because
of the combination between a short antagonist protocol
and a GnRH agonist trigger for the final oocyte
maturation. This approach has tremendously reduced
the incidence of OHSS in patients at risk [35], but it
does not eliminate the OHSS risk [36]. In conclusion,
the optimal COS strategy should balance the maintenance
of an optimal oocyte yield, with virtually zero risks
of iatrogenic complications [37].
According to guidelines, the response after conventional
ovarian stimulation (150 - 225 IU FSH) is classified as
low (≤ 3 follicles on day of oocyte maturation trigger
and/or ≤ 3 oocytes retrieved), normal, and high (> 18
follicles ≥ 11 mm on day of oocyte maturation trigger
and/or 18 oocytes obtained) [38, 39].
FP guidelines provide different options for ovarian
stimulation, taking into account the individualization

FARMACIA, 2021, Vol. 69, 2
194
of protocols. Medications that stimulate the ovaries
may be used to induce ovulation in patients with
anovulatory infertility or to hyper-stimulate the ovaries
in a controlled fashion in ovulatory patients as part
of assisted reproductive treatments (ART).
The main therapeutic agents used to stimulate ovarian
function include gonadotropins, pulsatile gonadotropin-
releasing hormone (GnRH), clomiphene citrate, and
letrozole. Adjuvant agents like glucocorticoids, aspirin,
androgens, metformin, coenzyme Q10 and sildenafil
are also discussed in terms of efficacy and safety.
Gonadotropins
Types of gonadotrophins available in ovarian stimulation
(OS) protocols include recombinant FSH (rFSH), human
menopausal gonadotropin (hMG), purified FSH (p-
FSH) and highly purified FSH (hp-FSH), recombinant
LH (rLH). Different associations of gonadotrophins
are recommended for specific patient groups for an
efficient and safe stimulation.
A total of 2108 studies were published in the last ten
years on OS and gonadotropins on the PubMed® data-
base, with 312 RCT and 125 SR/MA; 13 RCT on the
topic in the last year.
For normal responders in GnRH antagonist, GnRH
agonist and rHCG improve the oocyte maturity and
embryo grading [40].
There may be little or no difference in a live birth, the
incidence of multiple pregnancies, clinical pregnancy
rate, or miscarriage rate between urinary-derived
gonadotrophins and recombinant follicle-stimulating
hormone in women with polycystic ovary syndrome.
For human menopausal gonadotropin or highly purified
human menopausal gonadotrophin versus urinary
follicle-stimulating hormone, we are uncertain whether
one or the other improves or lowers live birth, the
incidence of multiple pregnancies, clinical pregnancy
rate, or miscarriage rate [41].
For every birth achieved with gonadotropins, a similar
increased risk of multiple gestations occurs. The
randomized clinical trial data do not support the use
of gonadotropin for OS-IUI in women with unexplained
infertility [42]. We found no distinct evidence of a
difference between rLH combined with rFSH and
rFSH alone in live birth rates or OHSS [43] nor a
difference between low doses of gonadotropins and
gonadotropins combined with oral compounds in
pregnancy outcomes compared with high doses of
gonadotropins in ovarian stimulation regimens [44].
The use of rFSH and hMG is equally recommended
for ovarian stimulation, with slightly higher efficiency,
but not considered clinically significant, with hMG
use in the live birth rate. No significant difference was
reported in the OHSS rate [45]. The use of rFSh and
pFSh or hpFSH in GnRH agonist protocol is equally
recommended. No significant difference in live birth
rate or OHSS rate is associated, but the use of rFSH
is preferable to pFSH or hpFSH [46]. HpFSH is not
preferable over hMG for ovarian stimulation in down-
regulation with GnRH agonist protocol, similar clinical
pregnancy rate and number of oocytes retrieved being
reported [47] rFSH + rLH use was associated with
similar pregnancy rate compared to hMG, and with a
higher risk of OHSS in GnRH agonist protocol [48].
Gonadotropin-releasing hormone (GnRH)
A total of 1015 studies were published in the last ten
years on OS and metformin on the PubMed® data-
base, with 172 RCT and 71 SR/MA; 8 RCT on the topic
last year. GnRH antagonist protocols are preferred
for ovarian stimulation in women undergoing FP for
medical reasons because they reduce the duration of
stimulation and enable triggering of oocyte maturation
with GnRH agonist reducing the risk of ovarian hyper-
stimulation syndrome (OHSS). GnRH antagonist protocol
is preferred in normal responders, with similar pregnancy
and live birth rates and decreased OHSS compared with
GnRH agonist protocol [49, 50]. In low responders, the
GnRH antagonist protocol is correlated with fewer
oocytes retrieved, similar pregnancy and live birth
rates, and a shorter length of treatment than GnRH
agonist protocol [51]. Also, in low responders, a
delayed start in antagonist GnRH protocol was a
potentially efficient choice [52]. In high responders,
the GnRH antagonist protocol is effective as GnRH
agonist protocol in terms of pregnancy rate and the
number of oocytes retrieved, and a significant decrease
of OHSS [50]. During GnRH antagonist protocol, an
increased progesterone level is independently associated
with a reduced pregnancy rate in low and normal
responders, but not in high responders’ women [53].
Clomiphene citrate (CC)
Clomiphene Citrate (CC) is a selective oestrogen
receptor modulator (SERM) with oestrogen receptor
agonist and antagonist properties. A total of 442 studies
were published in the last ten years on OS and
clomiphene citrate on the PubMed® database, with
108 RCT and 70 SR/MA; 6 RCT on the topic last year.
Current evidence does not recommend the use of CC
instead of FSH in ovarian stimulation. No studies are
available about the benefit of adding CC to gonadotropins,
equal pregnancy outcome being obtained in COH
protocol with CC or the conventional protocol in low
responders [54]. In women with PCOS for ovulation
induction, the late luteal phase administration of CC
might be more effective than conventional administration
[55]. CC is not an option in low responders because
of high costs and low efficiency, short GnRH agonist
protocol being the first option [56]. Clomiphene citrate
is more successful than tamoxifen as first-line therapy
for ovulation induction in women with PCOS [57].
Letrozole
A total of 225 studies were published in the last ten
years on OS and letrozole on the PubMed® database,
with 52 RCT and 31 SR/MA; 6 RCT on the topic in
the last year. Letrozole, an aromatase inhibitor agent,
increases the secretion of FSH and stimulates follicle
development and maturation. Letrozole should be

FARMACIA, 2021, Vol. 69, 2
195
considered the first option for ovulation induction in
PCOS women with anovulatory infertility as pregnancy
and live birth rates are improved, time to achieve a
pregnancy is shorter, and multiple pregnancies are at
risk lower compared to CC [58]. Similar ovulation
and pregnancy rate can be obtained in letrozole-
induced ovulation compared to gonadotropin protocol,
with limited adverse effects. In PCOS women with
CC resistance or failure, letrozole is an effective
ovulation option, with higher pregnancy rates than
CC administration combined with metformin [59, 60].
During the ovarian stimulation cycle, co-administration
of aromatase inhibitors (e.g., letrozole) in oestrogen-
sensitive diseases, such as breast cancer, endometrial
cancer, or systemic lupus disease (SLE) reduce oestradiol
levels and the proliferative effect of malignant cells,
without affecting oocyte yield [61, 62].
Adjuvant therapies on ovarian stimulation
Androgens. A total of 194 studies were published in the
last ten years on OS and androgens on the PubMed®
database, with 21 RCT and 12 SR/MA; no RCT on the
topic last year. Androgens increase antral follicles'
response to stimulation, especially in older-reproductive
age women, mediated by IGF-1. Inconsistent evidence
is available regarding testosterone or dehydroepi-
androsterone (DHEA) use before ovarian stimulation,
ovarian response, clinical outcomes, dosage, duration
and safety [63]. In poor responders, transdermal
testosterone's addition seems to increase pregnancy
and live birth rates [64]. In normal responders, DHEA
administration did not modify the ovarian response to
a standard low dose of gonadotrophin stimulation [65].
Metformin. A total of 114 studies were published in
the last ten years on OS and metformin on the
PubMed® database, with 28 RCT and 29 SR/MA. We
found 13 RCTs on the topic in the last year. Adjuvant
metformin use in women with PCOS undergoing
ovulation induction with gonadotropins may increase
the pregnancy and live birth rate [66]. Metformin is
better than placebo for ovulation rate, pregnancy,
and live birth rate, but with more gastrointestinal
upsets. Metformin plus CC improves ovulation and
pregnancy rate, with no difference in live birth rate or
multiple pregnancies, but with the cost of a higher
probability of gastrointestinal side effects than CC
alone. Available studies about metformin versus CC
use do not reveal statistically significant differences
for live birth, pregnancy, or ovulation rate [67].
Metformin compared to placebo in GnRH agonist
protocol reported no difference in a live birth, increase
pregnancy rate and significantly fewer oocytes retrieved
[68, 69]. In GnRH-antagonist protocol, metformin
decrease live birth rate, without effect on pregnancy
rate, with no impact on the number of oocytes retrieved
or OHSS incidence [68, 70].
Tamoxifen. A total of 34 studies were published in the
last ten years on OS and tamoxifen on the PubMed®
database, with 5 RCT and 7 SR/MA; no RCT on the
topic in the last year. Selective oestrogen receptor
modulator (e.g., tamoxifen) does not reduce estradiol
concentrations, but has an inhibitory action on the
oestrogen receptor in oestrogen-sensitive disease [63].
In inducing ovulation protocols, tamoxifen and
clomiphene citrate are equally effective [71]. In terms
of induction of ovulation cycles, a good effect will
be from the combination of tamoxifen with letrozole
[72]. In women with unexplained infertility, tamoxifen
does not increase the clinical pregnancy rate [73].
Glucocorticoids. A total of 25 studies were published
in the last ten years on OS and glucocorticoids on the
PubMed® database, with 4 RCT and 4 SR/MA; no
RCT on the topic in the last year. Glucocorticoids may
improve folliculogenesis and pregnancy rates, but
at the moment are insufficient data in the literature
to confirm the hypothesis [63]. The glucocorticoid
administration in women undergoing controlled ovarian
hyper-stimulation is not established [74], with no
support data of efficacy of methylprednisolone in
the correlation between OHSS incidence and clinical
outcomes [75]. Dexamethasone increased ovary
response to gonadotropin stimulation, suppressed
the progesterone secretion, and determined a higher
cumulative live-birth rate [76].
Aspirin. A total of 11 studies were published on the
last ten years on OS and aspirin on the PubMed®
database, with 4 RCT and 1 SR/MA; no RCT on the
topic in the last year. In anovulatory PCOS patients,
the addition of low-dose aspirin (LDA) to tamoxifen
improves ovarian stimulation response and pregnancy
rates [77]. Adjuvant LDA increased the number of
poor-quality embryos but not decreased the severity
of OHSS [78]. In women undergoing IVF, LDA
does not have a positive effect on the likelihood of
pregnancy [79].
Coenzyme Q10. A total of 8 studies were published
in the last ten years on OS and Coenzyme Q10 on
the PubMed® database, with 2 RCT and 1 SR/MA; no
RCT on the topic in the last year. Co-enzyme Q10
(CoQ10) – reverse oocyte quality and quantity in
age-related infertility and improves ovarian response
and embryo parameters in young women. In women
with poor ovarian reserve, the addition of CoQ10
increased ovarian stimulation response in IVF-ICSI
cycles [80]. In clomiphene-citrate-resistant PCOS
patients, the adjuvant of CoQ10 improves ovulation
and clinical pregnancy rates [81].
Sildenafil. A total of 4 studies were published in the
last ten years on OS and metformin on the PubMed®
database, with 2 RCT; no RCT on the topic in the last
year. Adjuvant sildenafil citrate did enhance ovulation
success rate and increased pregnancy rate [82] and
does not enhance ovarian receptiveness in previous
low ovarian response to controlled OHSS [83]. In
the case of clomiphene citrate failure, the vaginal
administration might enrich the potential of pregnancy
[84]. Also, it may be used to increase ovarian

FARMACIA, 2021, Vol. 69, 2
196
vascularization and live birth rates, but the RCT of
Ataalla et al. reported no significant difference in
the numbers of oocytes retrieved or pregnancy rates
with adjuvant sildenafil [83].
Conclusions
Unlike other medical conditions, fertility screening
must be performed over a more extended period for
the patients to improve the quality of life and
reproduction. During the lockdown, counselling therapy
was cancelled, or a follow-up appointment was replaced
with telemedicine consultation to diminish the exposure
to SARS-CoV-2. Real-data showed that fertility might
be influenced by infection with SARS-COV-2 - more
significantly in males. Patients COVID-19 positive
should avoid becoming pregnant or participate in any
fertility programs. Screening the patient (and partner)
at least at the beginning of the FP treatment seems
mandatory. It is necessary periodical testing of
healthcare workers from fertility clinics to avoid
nosocomial transmission. In Romania, FP practice is
regulated by the Code of Practices, with no specific
mentions regarding the ART register, indications for
freezing or funding, and inconsistent data regarding
the type of interventions, compared to other European
countries.
The objective assessment of the impact of COVID-19
on fertility must be subject to further clinical studies
assessing at least one year after the declaration of the
SARS-CoV-2 pandemic. In the next period, COVID-
19 has been, is, and will be an additional challenge
for fertility.
The gonadotropins are used for OS as part of ART
cycles. GnRH agonist and rHCG improve the oocyte
maturity and embryo grading, rFSH and hMG is equally
recommended for OS. In PCOS, Letrozole is superior to
CC for OS and CC is more successful than tamoxifen.
Similar ovulation and pregnancy rate can be obtained
in letrozole - induced ovulation compared to
gonadotropin protocol. Androgens, metformin, gluco-
corticoids, tamoxifen, aspirin, Coenzyme Q10, sildenafil,
may be used as adjuvants for OS with a efficacy but
lack proven efficacy. Further studies on adjuvant
therapies and complementary support are welcomed,
in order to ensure optimal condition in assisted
reproductive interventions for fertility preservation,
especially in gonadotoxic therapies.
Conflict of interest
The authors declare no conflict of interest.
References
1. Pantea Stoian A, Pricop-Jeckstadt M, Pana A, Ileanu
BV, Schitea R, Geanta M, Catrinoiu D, Suceveanu
AI, Serafnceanu C, Pituru S, Poiana C, Timar B,
Nitipir C, Parvu S, Arsene A, Mazilu L, Toma A,
Hainarosie R, Ceriello A, Rizzo M, Jinga V, Death by
SARS-CoV 2: a Romanian COVID-19 multi-centre
comorbidity study. Sci Rep., 2020; 10(1): 21613: 1-11.
2. Davidescu EI, Odajiu I, Ilie MD, Bunea T, Sandu G,
Stratan L, Iftode N, Aramă V, Popescu BO, Influence
of tocilizumab on the outcome of patients with
Covid-19. Retrospective observational study. Farmacia,
2020; 68(5): 792-799.
3. Arsene AL, Dumitrescu IB, Dragoi CM, Udeanu DI,
Lupuliasa D, Jinga V, Draganescu D, Dinu-Pîrvu CE,
Burcea Dragomiroiu GTA, Blejan IE, Moisi RE,
Nicolae AC, Moldovan H, Popa DE, Velescu BȘ,
Ruță S, A new era for the therapeutic management of
the ongoing COVID-19 pandemic. Farmacia, 2020;
68(2): 185-196.
4. Global IVF Services Market Report 2020: COVID-
19 Growth and Change Insights - Forecast to 2030 -
2020; www.businesswire.com/ 20201113005541.
5. Filip L, Duică F, Prădatu A, Crețoiu D, Suciu N,
Crețoiu SM, Predescu DV, Varlas VN, Voinea SC,
Endometriosis Associated Infertility: A Critical Review
and Analysis on Etiopathogenesis and Therapeutic
Approaches. Medicina (Kaunas), 2020; 56(9): 460:
1-23.
6. Lekovich J, Lobel ALS, Stewart JD, Pereira N, Kligman
I, Rosenwaks Z, Female patients with lymphoma
demonstrate diminished ovarian reserve even before
initiation of chemotherapy when compared with healthy
controls and patients with other malignancies. J Assist
Reprod Genet., 2016; 33(5): 657-662.
7. Morgan S, Anderson RA, Gourley C, Wallace WH,
Spears N, How do chemotherapeutic agents damage
the ovary?. Hum Reprod Update, 2012; 18(5): 525-
535.
8. Bârca M, Manda G, Ciobanu AM, Bălălău C, Lupuleasa
D, Burcea Dragomiroiu GTA, Pop A, Popa DE, Baconi
DL, Immunomodulatory effects of methadone following
methotrexate therapy in a rat model of arthritis.
Farmacia, 2017; 65(3): 423-428.
9. Chan JL, Wang ET, Oncofertility for women with
gynecologic malignancies. Gynecol Oncol., 2017;
144(3): 631-636.
10. Stanley KE, Thomas E, Leaver M, Wells D, Coronavirus
disease-19 and fertility: viral host entry protein expression
in male and female reproductive tissues. Fertil Steril.,
2020; 114(1): 33-43.
11. Patel DP, Punjani N, Guo J, Alukal JP, Li PS, Hotaling
JM, The impact of SARS-CoV-2 and COVID-19 on
Male Reproduction and Men’s Health. Fertil Steril.,
2021; 115(4): 813-823.
12. 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. J Ovarian Res.,
2020; 13(1): 140: 1-18.
13. Illiano E, Trama F, Costantini E, Could COVID-19
have an impact on male fertility?. Andrologia, 2020;
52(6): e13654: 1-3.
14. Segars J, Katler Q, McQueen DB, Kotlyar A, Glenn
T, Knight Z, Feinberg EC, Taylor HS, Toner JP,
Kawwass JF, Prior and novel coronaviruses, Coronavirus
Disease 2019 (COVID-19), and human reproduction:
what is known?. Fertil Steril., 2020; 113(6): 1140-
1149.

FARMACIA, 2021, Vol. 69, 2
197
15. Aitken RJ, COVID-19 and human spermatozoa-
Potential risks for infertility and sexual transmission?.
Andrology, 2021; 9(1): 48-52.
16. Vishvkarma R, Rajender S, Could SARS-CoV-2 affect
male fertility?. Andrologia, 2020; 52(9): e13712: 1-8.
17. Jing Y, Run-Qian L, Hao-Ran W, Hao-Ran C, Ya-Bin
L, Yang G, Fei C, Potential influence of COVID-
19/ACE2 on the female reproductive system. Mol
Hum Reprod., 2020; 26(6): 367-373.
18. European Society of Human Reproduction and
Embryology. News and Statements. Assisted reproduction
and COVID 19: An updated statement from ESHRE
17th April 2020,www.eshre.eu/Press-Room.
19. British Fertility Society/Association of Reproductive &
Clinical Scientists. Guidance for the care of fertility
patients during the Coronavirus COVID 19 Pandemic,
2020, www.britishfertilitysociety.org.uk/2020/03/18/.
20. Salama M, Ataman-Millhouse L, Braham M, Berjeb
K, Khrouf M, Rodrigues JK, Reis FM, Cury-Silva T,
Sánchez F, Romero S, Smitz J, Vásquez L, Vega
M, Sobral F, Terrado G, Lombardi MG, Scarella A,
Bourlon MT, Verduzco-Aguirre H, Sánchez AM,
Adiga SK, Tholeti P, Udupa KS, Mahajan N, Patil
M, Dalvi R, Venter C, Demetriou G, Geel J, Quintana
R, Rodriguez G, Quintana T, Viale L, Fraguglia M,
Coirini M, Remolina-Bonilla YA, Noguera JAR,
Velásquez JC, Suarez A, Arango GD, Pineda JID,
Aldecoa MDC, Javed M, Al Sufyan H, Daniels N,
Oranye BC, Ogunmokun AA, Onwuzurigbo KI,
Okereke CJ, Whesu TC, Woodruff TK, Installing
oncofertility programs for common cancers in limited
resource settings (Repro-Can-OPEN Study): An
extrapolation during the global crisis of Coronavirus
(COVID-19) pandemic. J Assist Reprod Genet., 2020;
37(7): 1567-1677.
21. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z,
Anticoagulant treatment is associated with decreased
mortality in severe coronavirus disease 2019 patients
with coagulopathy. J Thromb Haemost, 2020; 18(5):
1094-1099.
22. Grandone E, Villani M, Assisted reproductive
technologies and thrombosis. Thromb Res., 2015;
135(Suppl 1): S44-45.
23. Fabregues F, Peñarrubia J, Assisted reproduction and
thromboembolic risk in the COVID-19 pandemic.
Reprod Biomed Online, 2020; 41(3): 361-364.
24. Patel R, Babady E, Theel ES, Storch GA, Pinsky
BA, St George K, Smith TC, Bertuzzi S, Report from
the American Society for Microbiology COVID-19
International Summit, 23 March 2020: Value of
Diagnostic Testing for SARS-CoV-2/COVID-19.
mBio., 2020; 11(2): e00722-20: 1-5.
25. Vandenberg O, Martiny D, Rochas O, van Belkum A,
Kozlakidis Z, Considerations for diagnostic COVID-
19 tests. Nat Rev Microbiol., 2021; 19(3): 171-183.
26. Papathanasiou A, COVID-19 screening during fertility
treatment: how do guidelines compare against each
other?. J Assist Reprod Genet., 2020; 37(8): 1831-
1835.
27. La Marca A, Nelson SM, SARS-CoV-2 testing in
infertile patients: different recommendations in Europe
and America. J Assist Reprod Genet., 2020; 37(8):
1823-1828.
28. La Marca A, Capuzzo M, Paglia T, Roli L, Trenti T,
Nelson SM, Testing for SARS-CoV-2 (COVID-19):
a systematic review and clinical guide to molecular
and serological in-vitro diagnostic assays. Reprod
Biomed Online, 2020; 41(3): 483-499.
29. Pomeroy KO, Harris S, Conaghan J, Papadakis M,
Centola G, Basuray R, Battaglia D, Storage of
cryopreserved reproductive tissues: evidence that cross-
contamination of infectious agents is a negligible
risk. Fertil Steril., 2010; 94(4): 1181-1188.
30. Yakass MB, Woodward B, COVID-19: should we
continue to cryopreserve sperm during the pandemic?.
Reprod Biomed Online, 2020; 40(6): 905.
31. Dellino M, Minoia C, Paradiso AV, De Palo R,
Silvestris E, Fertility Preservation in Cancer Patients
During the Coronavirus (COVID-19) Pandemic. Front
Oncol., 2020; 10: 1009Ș 1-5.
32. Pomeroy KO, Schiewe MC, Cryopreservation and
IVF in the time of Covid-19: what is the best good
tissue practice (GTP)?. J Assist Reprod Genet., 2020;
37(10): 2393-3298.
33. Barragan M, Guillén JJ, Martin-Palomino N, Rodriguez
A, Vassena R, Undetectable viral RNA in oocytes
from SARS-CoV-2 positive women. Hum Reprod
Oxf Engl., 2021; 36(2): 390-394.
34. Bourdon M, Santulli P, Maignien C, Pocate-Cheriet
K, Marcellin L, Chen Y, Chapron C, The Ovarian
Response After Follicular Versus Luteal Phase Stimulation
with a Double Stimulation Strategy. Reprod Sci.,
2020; 27(1): 204-210.
35. Ovarian Stimulation for IVF/ICSI, 2021; www.eshre.eu.
36. Toftager M, Bogstad J, Bryndorf T, Løssl K, Roskær
J, Holland T, Prætorius L, Zedeler A, Nilas L, Pinborg
A, Risk of severe ovarian hyperstimulation syndrome
in GnRH antagonist versus GnRH agonist protocol:
RCT including 1050 first IVF/ICSI cycles. Hum
Reprod., 2016; 31(6): 1253-1264.
37. Coyne K, Purdy M, O’Leary K, Yaklic JL, Lindheim
SR, Appiah LA, Challenges and considerations in
optimizing ovarian stimulation protocols in oncofertility
patients. Front Public Health, 2014; 2: 246: 1-7.
38. Griesinger G, Verweij PJM, Gates D, Devroey P,
Gordon K, Stegmann BJ, Tarlatzis BC, Prediction
of Ovarian Hyperstimulation Syndrome in Patients
Treated with Corifollitropin alfa or rFSH in a GnRH
Antagonist Protocol. PloS One, 2016; 11(3): e0149615:
1-14.
39. Ferraretti AP, La Marca A, Fauser BCJM, Tarlatzis B,
Nargund G, Gianaroli L, ESHRE working group on
Poor Ovarian Response Definition, ESHRE consensus
on the definition of “poor response” to ovarian
stimulation for in vitro fertilization: the Bologna
criteria. Hum Reprod., 2011; 26(7): 1616-1624.
40. Ali SS, Elsenosy E, Sayed GH, Farghaly TA, Youssef
AA, Badran E, Abbas AM, Abdelaleem AA, Dual
trigger using recombinant HCG and gonadotropin-
releasing hormone agonist improve oocyte maturity
and embryo grading for normal responders in GnRH
antagonist cycles: Randomized controlled trial. J
Gynecol Obstet Hum Reprod., 2020; 49(5): 101728:
1-6.
41. Weiss NS, Kostova E, Nahuis M, Mol BWJ, van der
Veen F, van Wely M, Gonadotrophins for ovulation
induction in women with polycystic ovary syndrome.

FARMACIA, 2021, Vol. 69, 2
198
Cochrane Database Syst Rev., 2019; 1(1): CD010290:
1-71.
42. Zolton JR, Lindner PG, Terry N, DeCherney AH,
Hill MJ, Gonadotropins versus oral ovarian stimulation
agents for unexplained infertility: a systematic review
and meta-analysis. Fertil Steril., 2020; 113(2): 417-
425.
43. Mochtar MH, Danhof NA, Ayeleke RO, Van der Veen
F, van Wely M, Recombinant luteinizing hormone
(rLH) and recombinant follicle stimulating hormone
(rFSH) for ovarian stimulation in IVF/ICSI cycles.
Cochrane Database Syst Rev., 2017; 5(5): CD005070:
1-102.
44. Youssef MA-F, van Wely M, Mochtar M, Fouda UM,
Eldaly A, El Abidin EZ, Elhalwagy A, Abdallah
AAM, Zaki SS, Ghafar MSA, Mohesen MN, van
der Veen F, Low dosing of gonadotropins in in vitro
fertilization cycles for women with poor ovarian
reserve: systematic review and meta-analysis. Fertil
Steril., 2018; 109(2): 289-301.
45. Figen Turkcapar A, Seckin B, Onalan G, Ozdener T,
Batioglu S, Human Menopausal Gonadotropin versus
Recombinant FSH in Polycystic Ovary Syndrome
Patients Undergoing In Vitro Fertilization. Int J Fertil
Steril., 2013; 6(4): 238-243.
46. Sohrabvand F, Sheikhhassani S, Bagheri M, Haghollahi
F, Shabihkhani M, Shariat M, Esfahani MN, Comparison
of highly purified urinary versus recombinant FSH:
Effect on ART outcomes in polycystic ovary syndrome.
Iran J Reprod Med., 2012; 10(3): 229-236.
47. Parsanezhad ME, Jahromi BN, Rezaee S, Kooshesh L,
Alaee S, The Effect of Four Different Gonadotropin
Protocols on Oocyte and Embryo Quality and Pregnancy
Outcomes in IVF/ICSI Cycles; A Randomized
Controlled Trial. Iran J Med Sci., 2017; 42(1): 57-65.
48. Pacchiarotti A, Sbracia M, Frega A, Selman H, Rinaldi
L, Pacchiarotti A, Urinary hMG (Meropur) versus
recombinant FSH plus recombinant LH (Pergoveris)
in IVF: a multicenter, prospective, randomized controlled
trial. Fertil Steril., 2010; 94(6): 2467-2469.
49. Xiao J, Su C, Zeng X, Comparisons of GnRH
antagonist versus GnRH agonist protocol in supposed
normal ovarian responders undergoing IVF: a systematic
review and meta-analysis. PloS One, 2014; 9(9):
e106854: 1-10.
50. Lambalk CB, Banga FR, Huirne JA, Toftager M,
Pinborg A, Homburg R, van der Veen F, van Wely M,
GnRH antagonist versus long agonist protocols in
IVF: a systematic review and meta-analysis accounting
for patient type. Hum Reprod Update, 2017; 23(5):
560-579.
51. Xiao J, Chang S, Chen S, The effectiveness of
gonadotropin-releasing hormone antagonist in poor
ovarian responders undergoing in vitro fertilization:
a systematic review and meta-analysis. Fertil Steril.,
2013; 100(6): 1594-1601.
52. Yang S, Liu N, Li Y, Zhang L, Yue R, Efficacy of
the delayed start antagonist protocol for controlled
ovarian stimulation in Bologna poor ovarian responders:
a systematic review and meta-analysis. Arch Gynecol
Obstet., 2021; 303(2): 347-362.
53. Griesinger G, Mannaerts B, Andersen CY, Witjes H,
Kolibianakis EM, Gordon K, Progesterone elevation
does not compromise pregnancy rates in high
responders: a pooled analysis of in vitro fertilization
patients treated with recombinant follicle-stimulating
hormone/gonadotropin-releasing hormone antagonist
in six trials. Fertil Steril., 2013; 100(6): 1622-1628.
54. Song D, Shi Y, Zhong Y, Meng Q, Hou S, Li H,
Efficiency of mild ovarian stimulation with clomiphene
on poor ovarian responders during IVF\ICSI procedures:
a meta-analysis. Eur J Obstet Gynecol Reprod Biol.,
2016; 204: 36-43.
55. Ding N, Chang J, Jian Q, Liang X, Liang Z, Wang F,
Luteal phase clomiphene citrate for ovulation induction
in women with polycystic ovary syndrome: a systematic
review and meta-analysis. Gynecol Endocrinol., 2016;
32(11): 866-871.
56. Schimberni M, Ciardo F, Schimberni M, Giallonardo
A, De Pratti V, Sbracia M, Short gonadotropin-releasing
hormone agonist versus flexible antagonist versus
clomiphene citrate regimens in poor responders undergoing
in vitro fertilization: a randomized controlled trial. Eur
Rev Med Pharmacol Sci., 2016; 20(20): 4354-4361.
57. Badawy A, Gibreal A, Clomiphene citrate versus
tamoxifen for ovulation induction in women with
PCOS: a prospective randomized trial. Eur J Obstet
Gynecol Reprod Biol., 2011; 159(1): 151-154.
58. Bansal S, Goyal M, Sharma C, Shekhar S, Letrozole
versus clomiphene citrate for ovulation induction in
anovulatory women with polycystic ovarian syndrome:
A randomized controlled trial. Int J Gynaecol Obstet.,
2021; 152(3): 345-350.
59. Shi S, Hong T, Jiang F, Zhuang Y, Chen L, Huang X,
Letrozole and human menopausal gonadotropin for
ovulation induction in clomiphene resistance polycystic
ovary syndrome patients: A randomized controlled
study. Medicine (Baltimore), 2020; 99(4): e18383:
1-4.
60. Rezk M, Shaheen AE, Saif El-Nasr I, Clomiphene
citrate combined with metformin versus letrozole for
induction of ovulation in clomiphene-resistant polycystic
ovary syndrome: a randomized clinical trial. Gynecol
Endocrinol., 2018; 34(4): 298-300.
61. Badea M, Baros A, Bohiltea RE, Julea IE, Furtunescu
FL, Istrate-Ofiteru AM, Iovan L, Cirstoiu MM, Burcin
MR, Turcan N, Neacsu A, Berceanu C, Modern
interdisciplinary monitoring of cervical cancer risk.
Romanian J Morphol Embryol., 2019; 60(2): 469-478.
62. Oktay K, Türkçüoğlu I, Rodriguez-Wallberg KA,
GnRH agonist trigger for women with breast cancer
undergoing fertility preservation by aromatase inhibitor/
FSH stimulation. Reprod Biomed Online, 2010; 20(6):
783-788.
63. Quaas AM, Legro RS, Pharmacology of medications
used for ovarian stimulation. Best Pract Res Clin
Endocrinol Metab., 2019; 33(1): 21-33.
64. Noventa M, Vitagliano A, Andrisani A, Blaganje M,
Viganò P, Papaelo E, Scioscia M, Cavallin F, Ambrosini
G, Cozzolino M, Testosterone therapy for women
with poor ovarian response undergoing IVF: a meta-
analysis of randomized controlled trials. J Assist
Reprod Genet., 2019; 36(4): 673-683.
65. Yeung T, Chai J, Li R, Lee V, Ho PC, Ng E, A double-
blind randomised controlled trial on the effect of
dehydroepiandrosterone on ovarian reserve markers,
ovarian response and number of oocytes in anticipated

FARMACIA, 2021, Vol. 69, 2
199
normal ovarian responders. BJOG., 2016; 123(7):
1097-1105.
66. Bordewijk EM, Nahuis M, Costello MF, Van der
Veen F, Tso LO, Mol BWJ, van Wely M, Metformin
during ovulation induction with gonadotrophins followed
by timed intercourse or intrauterine insemination for
subfertility associated with polycystic ovary syndrome.
Cochrane Database Syst Rev., 2017; 1(1): CD009090:
1-49.
67. Sharpe A, Morley LC, Tang T, Norman RJ, Balen
AH, Metformin for ovulation induction (excluding
gonadotrophins) in women with polycystic ovary
syndrome. Cochrane Database Syst Rev., 2019; 12(12):
CD013505: 1-148.
68. Tso LO, Costello MF, Albuquerque LET, Andriolo
RB, Macedo CR, Metformin treatment before and
during IVF or ICSI in women with polycystic ovary
syndrome. Cochrane Database Syst Rev., 2020; 12:
CD006105: 1-10.
69. Abdalmageed OS, Farghaly TA, Abdelaleem AA,
Abdelmagied AE, Ali MK, Abbas AM, Impact of
Metformin on IVF Outcomes in Overweight and
Obese Women With Polycystic Ovary Syndrome: A
Randomized Double-Blind Controlled Trial. Reprod
Sci., 2019; 26(10): 1336-1342.
70. Jacob SL, Brewer C, Tang T, Picton HM, Barth JH,
Balen AH, A short course of metformin does not
reduce OHSS in a GnRH antagonist cycle for women
with PCOS undergoing IVF: a randomised placebo-
controlled trial. Hum Reprod., 2016; 31(12): 2756-
2764.
71. Steiner AZ, Terplan M, Paulson RJ, Comparison of
tamoxifen and clomiphene citrate for ovulation induction:
a meta-analysis. Hum Reprod., 2005; 20(6): 1511-
1515.
72. Pourmatroud E, Zargar M, Nikbakht R, Moramazi
F, A new look at tamoxifen: co-administration with
letrozole in intrauterine insemination cycles. Arch
Gynecol Obstet., 2013; 287(2): 383-387.
73. Shokeir TA, Tamoxifen citrate for women with
unexplained infertility. Arch Gynecol Obstet., 2006;
274(5): 279-283.
74. Kalampokas T, Pandian Z, Keay SD, Bhattacharya
S, Glucocorticoid supplementation during ovarian
stimulation for IVF or ICSI. Cochrane Database
Syst Rev., 2017; 3(3): CD004752: 1-30.
75. Mohammadi Yeganeh L, Moini A, Shiva M, Mirghavam
N, Bagheri Lankarani N, Methylprednisolone for
prevention of ovarian hyperstimulation syndrome in
patients with polycystic ovarian syndrome undergoing
in-vitro fertilisation: a randomised controlled trial.
J Obstet Gynaecol., 2018; 38(2): 241-246.
76. Liu S, Shi L, Wang T, Shi J, Effect of low-dose
dexamethasone on patients with elevated early follicular
phase progesterone level and pregnancy outcomes in
IVF-ET treatment: A randomized controlled clinical
trial. Clin Endocrinol (Oxf.), 2018; 89(6): 771-778.
77. Aref NK, Ahmed WAS, Ahmed MR, Sedik WF, A
new look at low-dose aspirin: Co-administration with
tamoxifen in ovulation induction in anovulatory PCOS
women. J Gynecol Obstet Hum Reprod., 2019; 48(8):
673-675.
78. Namavar Jahromi B, Zolghadri J, Rahmani E, Alipour
S, Anvar Z, Zarei A, Keramati P, Effect of low-dose
aspirin on the development of ovarian hyperstimulation
syndrome and outcomes of assisted reproductive
techniques in the women with PCOS, a randomized
double-blinded clinical trial. Taiwan J Obstet Gynecol.,
2019; 58(2): 255-260.
79. Gelbaya TA, Kyrgiou M, Li TC, Stern C, Nardo
LG, Low-dose aspirin for in vitro fertilization: a
systematic review and meta-analysis. Hum Reprod
Update, 2007; 13(4): 357-364.
80. Xu Y, Nisenblat V, Lu C, Li R, Qiao J, Zhen X,
Wang S, Pretreatment with coenzyme Q10 improves
ovarian response and embryo quality in low-prognosis
young women with decreased ovarian reserve: a
randomized controlled trial. Reprod Biol Endocrinol.,
2018; 16(1): 29: 1-11.
81. El Refaeey A, Selem A, Badawy A, Combined
coenzyme Q10 and clomiphene citrate for ovulation
induction in clomiphene-citrate-resistant polycystic
ovary syndrome. Reprod Biomed Online, 2014; 29(1):
119-124.
82. Aboelroose AA, Ibrahim ZM, Madny EH, Elmazzahy
AM, Taha OT, A randomized clinical trial of sildenafil
plus clomiphene citrate to improve the success rate
of ovulation induction in patients with unexplained
infertility. Int J Gynaecol Obstet., 2020; 150(1): 72-76.
83. Ataalla WM, abd Elhamid T, Elhalwagy AE, Adjuvant
sildenafil therapy in poor responders undergoing in
vitro fertilization: A prospective, randomized, double-
blind, placebo-controlled trial. Middle East Fertil Soc
J., 2016; 21(3): 175-179.
84. Soliman GM, Fetih G, Abbas AM, Thermosensitive
bioadhesive gels for the vaginal delivery of sildenafil
citrate: in vitro characterization and clinical evaluation
in women using clomiphene citrate for induction of
ovulation. Drug Dev Ind Pharm., 2017; 43(3): 399-408.