Heliyon 8 (2022) e11010

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Heliyon
journal homepage: www.cell.com/heliyon

Research article

An update of polycystic ovary syndrome: causes and therapeutics options

A R T I C L E I N F O A B S T R A C T

Keywords: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by menstrual irregularities, chronic
Polycystic ovary syndrome anovulation, hirsutism, androgenic alopecia, and acne. At diagnosis, patients can with different manifestations
Pharmacology according to the disease phenotype, patient’s age, and lifestyle. However, most patients pursue medical care
Infertility
because of the clinical symptoms of PCOS, such as hyperandrogenism, menstrual irregularities and infertility.
Anovulation
Amenorrhea
Recent studies have shown that PCOS is associated with 80% of anovulatory infertility; however, the precise
Hyperandrogenism mechanism of PCOS-induced anovulation is still undetermined. The treatment strategies of PCOS are symptomatic
Anti-müllerian hormone depending mainly on the desired goals and clinical benefits. Life style intervention is still the first line treatment
option for overweight females seeking pregnancy. In addition, there are many pharmacological agents that could
be added to induce ovulation such as metformin, and clomiphene citrate. Nowadays, many patients preferred to
use some herbal medicine that was proved to have potential therapeutic benefits in many studies in the man-
agement of PCOS. The purpose of this review was to discuss PCOS-induced infertility and the available thera-
peutic options as well as the impact of COVID-19 infection on the success of fertility attempts. To address this
purpose, Pubmed, Scopus, EMBASE and Google databases were searched for studies discussing PCOS-induced
infertility. The literature search revealed the proper therapeutic plans to treat PCOS-induced infertility, and
that treatment should be modified according to patient’s complaints, reproductive desires, and disease pheno-
types. In conclusion, the use of specific therapeutic agents and patients’ adherence to lifestyle interventions could
help patients recover their reproductive and metabolic health.

1. Introduction that more than 80% of females with symptoms of hyperandrogenism are
diagnosed with PCOS [6]. Additionally, 70–80% of females with PCOS
Polycystic ovary syndrome (PCOS) is the most common chronic complain of male-like pattern hirsutism of terminal hir grown on the
reproductive and metabolic endocrine disorder affecting women of lower face, chin, and neck [5, 8, 9]. In addition to hirsutism, women with
childbearing age, with prevalence estimated to be 4%–21% worldwide PCOS may present with alopecia. A retrospective cohort study showed
[1, 2]. It was first described by Hippocrates in 377–460 BC as “women that 22.4% of females with PCOS who were attending the PCOS multi-
whose menstruation is less than 3 days or meager are robust, with a disciplinary clinic in San Francisco (USA) had androgenic alopecia [10].
healthy complexion and a masculine appearance; yet they are not con- Acne is another clinical sign of hyperandrogenism but it is less prevalent
cerned about bearing children nor do they become pregnant” [3]. and specific than hirsutism [6]. Approximately 15%–25% of females with
Polycystic ovary syndrome is a heterogeneous disorder characterized PCOS present with acne [11]. The increased androgen levels in PCOS
by a triad of hyperandrogenism, menstrual irregularities and polycystic stimulates sebum production in the sebaceous gland [12] which can lead
ovaries. Therefore, patients can present with different manifestations of to moderate to severe acne [13].
this triad depending on the disease phenotype, patient’s age, and lifestyle Patients with PCOS may complain of oligomenorrhea, secondary
[5]. However, most patients seek medical care because of the clinical amenorrhea or dysfunctional uterine bleeding [14]. Approximately,
symptoms of hyperandrogenism, menstrual irregularities and infertility 85%–90% of females with oligomenorrhea and 30%–40% of females
[6]. with amenorrhea have PCOS [5]. In addition to infertility, can lead to
Clinical signs of hyperandrogenism that are frequently seen in PCOS serious complications such as metabolic syndrome, diabetes mellitus,
are hirsutism, androgenic alopecia, and acne [7]. A recent study showed dyslipidemia, endometrial cancer and cardiovascular disease [3]. Due to

* Corresponding author.
E-mail address: amrababah@just.edu.jo (A.M. Rababa’h).

https://doi.org/10.1016/j.heliyon.2022.e11010
Received 4 May 2022; Received in revised form 19 June 2022; Accepted 5 October 2022
2405-8440/© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
A.M. Rababa’h et al. Heliyon 8 (2022) e11010

these complications, PCOS is considered a metabolic reproductive syn- gonadotropin-releasing hormone (GnRH) neurons. Evidence from the
drome [4]. Thus, women with PCOS should be diagnosed early, treated literature showed that GnRH is disrupted in females with PCOS, and the
correctly and followed up carefully to avoid these detrimental effects. serum levels of AMH were generally increased [26]. Consequently, the
The evolving field of personalized medicine is playing an increasingly pathophysiology of infertility in women with PCOS could involve the
important role in the clinical management of patients with PCOS. Iden- disturbances of AMH-dependent regulation of GnRH release.
tification of single nucleotide polymorphisms (SNPs) in relevant genes Obesity accounts for 90% of infertility cases of PCOS [3]. It is an
permits the use of screening genetic testing to predict the efficacy of independent factor of infertility and may cause many obstetric compli-
various therapies and to avoid treatment-limiting toxicities [15, 16]. The cations [27]. Adiposity (body mass index (BMI) > 30 kg/m2) is correlated
aim of the present review is to describe PCOS as a multifaceted condition with anovulation, causing a higher risk for infertility due to increase in
and to demonstrate the available therapeutic plan for the treatment of the androgen concentration [28]. Weight reduction in obese females with
PCOS-induced infertility. In addition, the emerging evidence of the PCOS leads to improving the menstrual cycle and fertility due to the
usefulness of personalized therapy and the related genetic basis are dis- reduction in circulating insulin and androgen levels.
cussed in this review.
2.2. Diagnosis of polycystic ovary syndrome and infertility
2. Methods
There are three valid diagnostic criteria for PCOS. The first diagnostic
A comprehensive search was conducted using PUBMED, SCOPUS
criteria was established by the National Institute of Health (NIH) in 1990.
EMBASE and Google databases for studies discussing the PCOS-induced
This criteria was broadened in 2003 to involve additional clinical fea-
infertility managements in the last 11 years. Mesh headings included
tures and is referred to as the Rotterdam criteria. Finally, the Androgen
polycystic ovary syndrome (PCOS), PCOS-induced infertility, PCOS and/
Excess and Polycystic Ovary Syndrome Society (AE-PCOS) developed a
anovulatory infertility, hyperandrogenism, PCOS and menstrual irregu-
new set of diagnostic criteria in 2006 [5,29]. However, the Rotterdam
larities, and infertility. Three authors (AR, BM, AY) conducted the search
criteria remains the most used among physicians of various specialties
and independently screened eligible titles to obtain articles for full-text
[30].
review. Abstracts were reviewed for all articles collected through the
The diagnosis of PCOS using Rotterdam criteria requires having two
electronic search process. Articles unrelated to the main topic, duplicates,
out of the following three findings: clinical/biochemical hyper-
and conference abstracts were excluded from the review process. Only
androgenism, oligo/amenorrhea and the appearance of polycystic ovary
articles published in English were considered. The titles and abstracts of
[31]. Clinical features of hyperandrogenism are acne, hirsutism or
the retrieved articles were screened, after which the full text of poten-
androgenic alopecia while biochemical changes involve high total, free
tially relevant articles were printed and read. Next, a reference search of
or bioavailable testosterone level [9]. Oligomenorrhea is defined as
these relevant articles was performed.
having menstrual periods with an interval of more than 35 days or five to
nine menstrual cycles per a year [32]. Amenorrhea is defined by a lack of
2.1. Pathophysiology of PCOS- induced infertility
menses for three or more consecutive months [33]. Polycystic ovary
morphology is determined using ultrasound by the appearance of 20 or
Hirsutism and infertility are the principal reasons that cause a patient
more follicles (2–9 mm in diameter) per ovary and/or ovarian volume is
with PCOS to seek medical attention. Polycystic ovary syndrome ac-
greater than 10 ml [34].
counts for 80% of anovulatory infertility [17, 18]. Generally, most pa-
In addition, the diagnosis of PCOS is exclusionary which means that
tients with PCOS-induced anovulation have irregularities in their
physicians have to rule out other common diseases that share similar
menstrual cycle, commonly amenorrhea or oligomenorrhea, combined clinical, biochemical, and morphological presentations. This includes
with hyperandrogenism. The precise mechanism of PCOS-induced
thyroid disorders, hyperprolactinemia, and non-classis congenital adre-
anovulation is undetermined; however, there is evidence to support the nal hyperplasia [35]. For example, patients with primary hypothyroidism
hypothesis that early maturation of some follicles in polycystic ovaries
could present with irregular menses, infertility, and excess weight. A
lead to arrested antral follicle growth [19, 20]. Anovulation in PCOS is mild increase in free and total testosterone, free and total estradiol,
characterized by the inability of assortment of the dominant follicles in
prolactin, and LH may be found in the laboratory tests of these patients.
granulosa cells which causes arrest of follicle advancement [20]. This Furthermore, ovarian morphological changes like bilateral multicystic
will cause an increase in estradiol (and progesterone) production that
appearance can be seen frequently on ultrasound [36].
could suppress the endogenous follicular stimulating hormone (FSH). According to the Rotterdam criteria, there are four PCOS phenotypes
Gorry et al. suggested that the environment of granulosa cells in PCOS
(Table 1). The classic phenotype includes the presence of both hyper-
females could lead to an anomalous interface between insulin and androgenism and ovulatory dysfunction with (A) or without (B) poly-
luteinizing hormone (LH) [19]. They justified their theory with evidence
cystic ovary morphology. However, females who ovulate normally have
showing that the increase in LH secretion relates to hyperinsulinemia, “ovulatory phenotype” (C). The “non-hyperandrogenic phenotype” is the
which is characteristic of the anovulatory female with PCOS [19, 21]. In
fourth type in which ovulatory dysfunction presents with polycystic
addition, women with PCOS were found to be more prone to metabolic ovaries without overt hyperandrogenism [37].
disorders such as diabetes mellitus and dyslipidemia compared to women
Infertility is defined as a couple’s inability to conceive after 12
without PCOS [22, 23]. The prevalence of glucose intolerance and dia- months of regular unprotected sexual intercourse due to abnormal
betes mellitus were reported to be 23%–35% and 4%–10%, respectively
reproductive capacity [38]. It is often interchangeable with subfertility
[24]. Conversely, it had been shown previously in vitro that the granulosa
cells’ steroidogenic effect to LH is mainly increased by the accumulation
of insulin [19], suggesting that insulin is a key determinant in arresting Table 1. The four phenotypes of polycystic ovary syndrome.
the antral follicles growth.
Anti-Müllerian hormone or Müllerian-inhibiting hormone (AMH or Clinical/ Ovulatory Polycystic
biochemical dysfunction ovaries
MIH) is a glycoprotein hormone released from the granulosa cells of hyperandrogenism
preantral and small antral follicles in women. In addition to its major role
Phenotype A ✓ ✓ ✓
on the hypothalamic–pituitary–gonadal axis, AMH has an important
Phenotype B ✓ ✓ —
function in both gonadal function and sexual differentiation [25]. AMH
Phenotype C ✓ — ✓
can serve as a molecular biomarker for PCOS and comparative size of the
Phenotype D — ✓ ✓
ovarian preserve. AMH receptors are expressed in the

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[39]. The most common cause of female infertility is ovulatory resistance in females with PCOS after vigorous exercise [53]. Further-
dysfunction [40]. Polycystic ovary syndrome is considered the most more, lifestyle modifications are associated with a significant improve-
frequent contributory factor of anovulation among females with infer- ment in the reproductive abnormalities associated with PCOS. A
tility risk approximated to be 15-fold higher in females diagnosed with randomized clinical trial conducted at Penn State University between
this syndrome [11, 41]. Females having PCOS often complain of oli- October 2008 and March 2014 on infertile females with PCOS who
goovulation or anovulation so there will be no ready mature egg every visited the Academic Health Centre compared the efficacy of precon-
month to be fertilized [41]. In addition, they are more likely to develop ception lifestyle intervention, combined oral contraception (OCP) and
complications such as preeclampsia, preterm labor and gestational dia- the combined treatment strategies on both reproductive and metabolic
betes which are associated with reproductive failure [42]. abnormalities. It was shown that weight loss through lifestyle changes
Infertile women with PCOS should undergo an infertility workup that was associated with higher ovulation (P < 0.05) and live birth rates (P ¼
includes medical history, physical examinations, imaging and laboratory 0.13) compared to OCP [3].
tests to exclude other causes of infertility [43]. The most important The mental health of women with PCOS is also a very important issue
laboratory workup is presented in Table 2. because they are more susceptible to depression and anxiety. Sleep dis-
orders play a role in the etiology and the development of mental health
2.3. Management of PCOS- induced infertility problem in these females [54]. Moreover, not getting enough sleep can
cause metabolic and endocrine changes such as decreased glucose
Infertility is the main reason for most ob/gnecology clinic visits by tolerance, decreased insulin sensitivity, increased evening concentrations
females complaining of PCOS. Fortunately, with the advancing scientific of cortisol, decreased levels of leptin and increased hunger and appetite
evidence-based therapeutic approach, there are many successful non- [55]. Therefore, it is recommended to refer patients who are suffering
pharmacological and pharmacological treatments of PCOS-induced from sleep disturbances to a physician who are specialize in the diagnosis
infertility. The main intent of these treatment strategies is ovulation in- and the treatment of sleep disorders [56]. The results of studies that
duction. In the current review, we will discuss the role of lifestyle mod- focused on lifestyle management are very promising and proved that this
ifications, medications, herbal medicine, and assissted reproductive strategy has a significant impact on the disease course while being
techniques in the management of PCOS-induced infertility. cost-effective. Physicians should encourage those who are suffering from
PCOS to start making positive changes in their daily lifestyle to enhance
2.4. Lifestyle modifications and maintain weight loss as well as to prevent weight gain.

Weight loss is considered the first line treatment for obese females 2.5. Ovulation induction medications
with PCOS seeking pregnancy [44, 45, 46]. Weight loss through lifestyle
interventions is considered the first line treatment for all overweight or 2.5.1. Clomiphene citrate
obese female (BMI >25 kg/m2) with PCOS [1, 17]. Conversely, pre- Clomiphene citrate (CC) is a selective estrogen receptor modulator
venting weight gain is necessary for lean women (BMI<25 kg/m2). and the most commonly used drug to induce ovulation in female with
Several studies have shown that weight reduction of at least 5–10% of the polycystic ovary syndrome [57]. Clinically, it competitively antagonizes
total body weight can improve metabolic, psychological as well as the estrogen receptor in the hypothalamus to increase the release of
reproductive disturbances associated with PCOS [47, 48]. These results gonadotropin releasing hormone [43]. Higher GnRH results in a higher
have been associated with decreased insulin insensitivity, reduction of production and secretion of FSH from the pituitary gland which stimu-
androgen levels, and restoration of ovulation [49]. lates follicles growth and recruitment [43]. The recommended initial
Lifestyle modifications should involve eating a healthy hypocaloric dose of CC is 50 mg/day orally started about the 2nd to the 5th day of
diet (1200–1400 kcal/day) and engaging in regular physical exercise for menstrual cycle for 5 days [58]. Ovulation often happens 5–10 days after
at least 120 min/day for 3–5 days/week [44]. Patients should be the end of the treatment. The dose can be increased by 50 mg/day if
encouraged to decrease the consumption of saturated fats and refined ovulation doesn’t occur in the previous cycle [58].
carbohydrates while increasing protein rich foods to promote satiety and Approximately, 80% of females ovulate after CC treatment [49]. The
improve insulin sensitivity [50]. It was found that diets rich in saturated effects of CC were compared to placebo in three randomized clinical
fatty acids promotes lipopolysaccharide-mediated inflammation by trials in anovulatory women and the results were summarized in a
increasing serum levels of tumor necrosis factor-alpha (TNF-α) and pe- meta-analysis. This meta analysis showed higher clinical pregnancy rate
ripheral leukocytic suppression of cytokine-3 (SOCS-3) expression [51]. in all CC treated groups in comparison with placebo [59]. However, the
A low glycemic diet has the ability to reduce insulin resistance, fasting long half-life of this drug, approximately two weeks, results in
insulin, total cholesterol, low density lipoprotein (LDL), androgen level, long-lasting side effects on endometrial development and cervical mucus
and waist circumference (WC) in PCOS females when compared to high [60]. In addition, it was estimated that 15%–20% of females with PCOS
glycemic diet [52]. Additionally, a recent systematic review showed are resistant to CC and don’t respond to a dose up to 150 mg/day for 5
significant improvement in BMI, WC, fasting insulin, and insulin days up to at least three treatment courses [46, 61]. However, the pres-
ence of such factors did not affect the use of CC as a first attempt of
conception. Furthermore, there are still many recommendations from
Table 2. Summary of the most common laboratory tests ordered for infertile gynecologists to use CC as a first line treatment of anovulatory infertility
females. in PCOS patients when no other infertility factors exist as it results in a
Laboratory Tests high ovulation percentage if administered correctly.
Follicular stimulating hormone (FSH)
Leutinizing hormone (LH) 2.5.2. Letrozole
Estradiol Letrozole is an aromatase inhibitor drug that works by reversibly
Progesterone
inhibiting the aromatization of androgens into estrogen. As a result, this
increases FSH secretion from pituitary gland by inhibiting the negative
Testosterone
feedback loop of estrogen on the hypothalamus [62]. Letrozole is given in
Sex hormone binding globulin
a dose range of 2.5–7.5 mg/day starting around the third to seventh day
Prolactin
of the menstrual cycle for five days [63, 64]. Currently, letrozole is
Thyroid stimulating hormone (TSH)
preferred over CC for ovulation induction for two main reasons. First,
Antimüllerian hormone (AMH)
letrozole has a higher ovulation rate (61.7% vs. 48.3%) and live birth rate

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(27.5% vs. 19.1%) compared to CC in infertile women with PCOS [65]. metformin and may contribute to variation in response to the drug [15].
Secondly, letrozole is associated with fewer side effects because of its A previous study that included 87 PCOS and 113 control women
higher elimination rate and short half-life [66]. However, it is being used analyzed the impact of OCT1 rs683369 and rs628031 polymorphisms
off label as it has not been approved for infertility treatment by the Food [85]. The results revealed that the SNP frequencies were not associated
and Drug Administration yet. Despite this disadvantage, letrozole should with the glucose tolerance test (OGTT) readings at baseline. However,
still be considered because of its advantages over other medications and PCOS patients with the G allele of OCT1 rs683369 and/or with the A
is an important alternative in the case of CC resistance. allele of OCT1 rs628031 had increased insulin sensitivity in comparison
to those with the wild-type genotype after receiving treatment. Other
2.5.3. Metformin candidate genes have recently been proposed in the literature, including
Metformin is the most widely used insulin sensitizer agent in the FSHR (follicle-stimulating hormone receptor) [86], and AR androgen
management of PCOS. In addition to improving insulin sensitivity, met- receptor [87]. Large prospective and randomized trials are needed: (i) to
formin reduces androgen levels by decreasing androgen and LH secretion establish gene-based treatemnt guidelines; and (ii) to understand the
from the ovaries and pituitary respectively and increasing sex hormone- interplay between different polymorphisms and other environ-
binding globulin (SHBG) production in the liver [49, 67]. Several clinical mental/lifestyle factors [88, 89].
trials demonstrated significantly higher ovulation rates with metformin
compared to placebo in females with PCOS [68, 69, 70]. Additionally, a 2.7. Herbal medicine as adjunctive therapy
meta-analysis of randomized placebo-controlled trials reported an
improvement in the clinical pregnancy rates and the live birth rates Herbal medicine is one type of complementary and alternative med-
among females taking metformin [71]. Furthermore, compared to icine and its use by women has increased significantly in the last decade
clomiphene citrate (CC) alone the addition of metformin to CC was [90]. According to the literature, two out of five females with PCOS use
associated with higher clinical pregnancy and ovulation rates [72]. herbal medicine to alleviate symptoms [91].
The usual metformin dose used for ovulation induction is 1500–2500 Cinnamon is a herbal remedy that is used widely in traditional health
mg/day divided between two to three doses [62]. The most common side practice to regulate the menstrual cycle of patients with PCOS. This
effects of metformin are nausea, abdominal pain, diarrhea and flatulence, popular practice was supported by several clinical studies [90, 91, 92]. A
which are associated with limited consequent compliance [73]. These dehydroepiandrosterone (DHEA)-induced PCOS mice model showed that
side effects can be prevented by prescribing extended-release tablets or the cinnamon treated group had restored cyclicity and ovarian
taking metformin with food [74]. The potential reproductive benefits of morphology [93]. Improving metabolic risk factors is another beneficial
metformin has gained much interest in the last decades as its ability to effect of cinnamon use that was demonstrated in a double-blinded ran-
improve insulin resistance blocks an important factor in the pathogenesis domized controlled clinical trial [94]. This clinical study showed that
of PCOS. Furthermore, the addition of metformin to CC has been shown cinnamon supplementation significantly reduced weight, fasting blood
to be synergistic. sugar (FBS), fasting insulin, total cholesterol, and LDL levels in females
with PCOS compared to placebo [94]. Deecreased insulin resistance and
2.5.4. Gonadotrophins increased high density lipoprotein (HDL) level were also reported [94].
Gonadotrophins are hormones endogenously produced by the pituitary Curcumin is one of the active ingredients found in the rhizome of
gland and used as a second line agents to induce ovulation when there is no tropical herb turmeric (Curcuma longa Linn) [95]. It is a food additive
response to CC [75]. It acts by stimulating follicles growth and develop- and coloring agent with a bright orange-yellow color [96]. Curcumin
ment in the ovaries [75]. Highly purified urinary-derived FSH, recombi- possesses various biological activities including antioxidant,
nent FSH and highly purified human menopausal gonadotrophin are the anti-inflammatory, anti-microbial, anti-tumor, cardioprotective and
main gonadotrophins available on the market [76]. The most commonly neuroprotective effects involving multiple mechanisms [97]. This wide
encountered disadvantages of these agents are an increased risk of ovarian range of pharmacological activities promotes studying its potential effect
hyperstimulation syndrome and multiple pregnancies [77]. in PCOS. A rat model of estradiol valerate-induced PCOS showed that
PCOS groups treated with an intraperitoneal injection of curcumin had
2.6. Single nucleotide polymorphisms in the treatment of PCOS significantly lower levels of interleukin-6 (IL-6) and C-reactive protein
(CRP) compared with untreated PCOS groups [98]. Additonally, a lower
Pharmacogenomics is an important approach for improving medica- expression of TNF-α in the ovaries was observed [98]. Evidence of cur-
tion selection, reducing adverse effects, improving patient compliance, cumin’s antioxidant activity was also shown in sodium arsenite-induced
and saving health care costs [78]. Although treatment with metformin is ovarian oxidative injury in mice [99]. Curcumin was able to significantly
recommended as a first-line drug therapy to induce ovulation in patients decrease reactive oxygen species and malondialdehyde levels in ovaries
with PCOS, it failed to achieve therapeutic goals in 20% of patients [79]. as well as increase super oxide dismutase level [99]. Interestingly, cur-
With the current level of evidence, PCOS patients may potentially benefit cumin can also decrease the serum insulin level and improve quantitative
from genetic testing. For example, polymorphisms in the STK11 (or insulin sensitivity check index [100].
LKB1) and OCT1 (organic cation transporter 1) genes have an impact on Marjoram is another herbal medicine that is traditionally used by
metformin pharmacodynamics and pharmacokinetics, respectively [80]. females with PCOS to restore menstrual regularity. Although there are
These polymorphisms may be useful for identifying metformin non- not enough studies that investigate the potential effect of marjoram, a
responders, who may benefit from an alternative treatment. Liver STK11 clinical randomized controlled pilot study showed the ability of marjo-
(or LKB1), also known as liver kinase B1 (LKB1), is a regulator of insulin ram to reduce adrenal androgen level and improve insulin sensitivity
sensitivity and glucose homeostasis [81]. In PCOS women, carriers of the [101]. In the DHEA-induced PCOS rat model, the marjoram treated group
G allele, heterozygous genotype (CG), a mutant genotype (GG) of STK11 had significantly lower estradiol levels and improved insulin sensitivity
rs8111699 SNP, had a significant improvement in ovulatory frequency in [73]. Additionally, marjoram showed the ability to reduce ovary weight
comparison to those with the wild genotype (CC) [82]. Restoring which suggests a reduction in the number of ovarian cysts [73]. Finally,
ovulation is a key part of treating many patient complaints, including there was evidence of anti-inflammatory and antioxidant effects of
infertility, abnormal or no uterine bleeding, and reducing hyper- marjoram which would target the proposed pathogenetic mechanism of
androgenic symptoms such as hirsutism, acne, and alopecia [83]. PCOS [73].
On the other hand, polymorphisms in the OCT1 gene affect metformin Thus, herbal medicine is a valuable option in the management of
pharmacokinetics. OCT1 mediates drugs transport in the liver [84]. Ge- PCOS. Gynecologists have reported increased tendencies for the use this
netic variation in OCT1 gene was linked to reduced hepatic uptake of type of complementary medicine. This is mostly connected to the results

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of previously mentioned studies that support the utility of these prom- With the recent outbreak of coronavirus disease of 2019 (COVID-19),
ising alternative medicines. Many of these herbs are effective on both the we cannot ignore its impact on all aspects of life. A question may cross the
reproductive and the metabolic disturbances that accompany PCOS and mind of couples who are planning for IVF: could COVID-19 infection
have minimal side effects compared to the long term use of the con- affect the success of IVF cycle attempts? An observational study was
ventional treatments [102]. conducted in a tertiary, university-affiliated medical center to assess the
influence of COVID-19 infection on patient’s performance during IVF.
2.8. Surgical management Patient’s stimulation characteristics and embryological variables of sub-
sequent IVF attempts before and after COVID-19 infection were compared
Surgical interventios provide an alternative opportunity for patients [116]. This research demonstrated that the patient’s performance and
who are unresposive to the conventional medical therapy. Laparoscopic ovarian reserve were not affected in the immediate subsequent IVF cyle
ovarian drilling (LOD) [103] is a minimally invasive surgical approach after recovering [116]. However, reduced proportion of top-quality em-
that is used to treat PCOS-associated infertility after the failure of the bryos (TQE) was observed, therefore the authors suggested three months
medical options. In this procedure, perforations in the surface of the interval (time needed for folliculogenesis and spermatogenesis) before
ovary and the stroma are done by either laparoscopic ovarian electro- resuming the IVF cycle [116]. Another study investigated the changes on
cautery (diathermy either by unipolar or bipolar) or laser vaporization IVF cycle parameters and obstetric outcomes after COVID-19 exposure for
using carbon dioxide (CO2), argon, or neodymium-doped yttrium both spouses. The result revealed that there were no significant differ-
aluminum garnet crystal lasers [104]. LOD works by two proposed ences in serum estradiol level, oocyte number, endometrial thickness,
mechanisms: loosening the condensed cortical layers of the polycystic fertilization rate and number of TQE [117]. However, sperm concentra-
ovary and destroying the ovarian follicles and stroma that are responsible tion was markedly reduced [117]. The dissemination of COVID-19 vac-
for androgen production which reduces plasma androgen levels and cines and then considering it mandatory for all necessitated studies
normalizes the hypothalamus pituitary axis [105]. investigating the possible adverse effects of these vaccines on pregnant
In a clinical trial, fifty infertile PCOS females who are resistent to CC females especially for assisted reproductive techniques like IVF. Fortu-
were included to study the effect of LOD on the hormonal profiles. Blood nately, COVID-19 mRNA vaccines are safe and were not shown to have a
samples were taken to measure serum testosterone, LH, and FSH levels negative effect on reproductive potential [118]. According to a retro-
before and after LOD. The results showed that LOD significantly reduced spective cohort study, this is because pregnancy outcome and the
testosterone, LH and the LH/FSH ratio [106]. Additionally, LH increases response to controlled ovarian stimulation were the same in vaccinated
FSH and improves the rate of ovulation and clinical pregnancy [106]. and unvaccinated females who undergone IVF [118].
This surgical approach has shown a lower risk of ovarian hyperstimula- Conversely, the treatment of many couples who were undergoing IVF
tion syndrome (OHSS), multiple pregnancy, lower cycle cancellation was interrupted or postponed during COVID-19 quarantine. These cou-
rates in patients later submitted to IVF and, thus, fewer direct and indi- ples were significantly psychologically affected. For that reason, fertility
rect costs in comparison with medical therapy [107]. centres were advised to support their patients to remain psychological
Bariatric surgery is a surgical procedure that is done to reduce body and physically fit to the next attempt [119].
weight for obese females with PCOS. Obesity plays an important role in
the pathogenesis of PCOS, therefore, weight loss through bariatric sur- 3. Conclusion
gery could cause dramatic physical and hormonal changes in these pa-
tients [108]. Physicians usually reserve this procedure for females who In conclusion, the results of this narrative review discussed various
did not respond to other interventions such as lifestyle modifications and studies dealing with the available treatment options for PCOS-induced
traditional medications [109]. A cohort study conducted on 36 infertile infertility. Many successful non-pharmacological and pharmacological
women with PCOS and obesity after undergoing bariatric surgery eval- treatments have been developed to treat this problem. Although ovula-
uated them 6 months and one year after surgery. The results revealed a tion induction is still the main intent of these treatment strategies, pa-
significant decrease in body mass index, free androgen index, free and tients’ adherence to lifestyle interventions plays a major role in
total testosterone levels along with an increase in sex hormone binding recovering their reproductive and metabolic health. For patients who did
globulin [110]. A reduction in the volume of the ovaries by ultrasound not respond to the first line agents, gonadotrophins are the proposed next
was also observed [110]. step. Finally, assisted reproductive technique and LOD are alternative
options for those who have failed ovulation induction therapy or have
2.9. Assisted reproductive techniques additional infertility factors. Bariatric surgery could be used to reduce
body weight for obese females with PCOS when other solutions did not
Artificial insemination and in-vitro fertilization (IVF) are the most work. While there are many studies that explored the role of various
popular types of assisted reproductive techniques. They are mainly used herbal medicines in the management of this condition, further clinical
for infertile females with PCOS who are resistant to ovulation induction studies are required to investigate the reproductive effect of herbs in
medication or when PCOS is accompanied by men's infertility factor or PCOS-induced infertility.
tubular damage [62]. In artificial insemination, a collected amount of
sperm from the male will be inserted into the cervix or the uterus of the Declarations
female around the ovulation time [111]. While in IVF, the ovaries will be
stimulated to produce a large number of follicles, then oocyte retrieval Author contribution statement
will be done and then fertilized by a collected sperm of the male in a
controlled environment in the laboratory [112]. Once embryos develop, Abeer M Rababa'h and Bayan Matani: Conceived and designed the
they will be transferred to be implanted in the uterus. experiments; Analyzed and interpreted the data; Contributed reagents,
The IVF success rate is estimated to be 50% in females younger than materials, analysis tools or data; Wrote the paper.
35 years old [113]. However, it could be associated with a serious OHSS. Alaa Yehya: Analyzed and interpreted the data; Contributed reagents,
OHSS manifests as ovarian enlargement, abdominal ascites and intra- materials, analysis tools or data; Wrote the paper.
vascular hemoconcentration due to the increased vascular permeability
[114]. There are some suggested preventive strategies to reduce the risk Funding statement
of OHSS. These include concomitant use of aspirin during ovarian stim-
ulation, the use of GnRH antagonist instead of GnRH agonist to prevent This research did not receive any specific grant from funding agencies
ovulation and avoid aggressive ovarian stimulation [115]. in the public, commercial, or not-for-profit sectors.

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A.M. Rababa’h et al. Heliyon 8 (2022) e11010

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Recent advances in the understanding and management of polycystic ovary
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anti-Mullerian hormone in the regulation of GnRH neuron excitability and
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