Polycystic Ovarian Syndrome and Fertility - BINASSS
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 64, Number 1, 65–75
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Polycystic Ovarian
Syndrome
and Fertility
JESSICA A. LENTSCHER, MD,*† BREONNA SLOCUM, MD,‡
and SAIOA TORREALDAY, MD*
*Walter Reed National Military Medical Center; †Program of
Reproductive Endocrinology and Infertility, Eunice Kennedy Shriver
National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, Maryland;
and ‡Department of Obstetrics and Gynecology, Georgetown
University, Washington, District of Columbia
Abstract: Polycystic ovary syndrome (PCOS) is a covered in detail in a previous chapter. PCOS
common endocrinopathy that has been associated with is characterized by chronic anovulation, clin-
impaired fertility. This chapter reviews the underlying
pathophysiology of PCOS and the associated fertility ical or biochemical hyperandrogenism, and
barriers of the condition. Psychologic concerns, hypo- polycystic ovaries. PCOS is associated with
thalamic-pituitary, ovarian, and mitochondria dysfunc- several clinical manifestations including obe-
tion, obesity, and the role of vitamin D in PCOS are sity, impaired glucose tolerance, metabolic
considered with respect to fertility. Lastly, pregnancy syndrome, type 2 diabetes mellitus (DM),
risk factors associated with PCOS are also reviewed.
Key words: polycystic ovary syndrome, infertility, anov- dyslipidemia, and cardiovascular disease2; the
ulation, hyperandrogenism, vitamin D, pregnancy severity and presentation of these symptoms
may vary widely among the population and
within an individual over time. The etiology
of PCOS is unknown and unfortunately,
there is no cure. Current management is
Introduction dependent on the treatment of symptoms
Polycystic ovarian syndrome (PCOS) is the and mitigation of risk factors for associated
most common female endocrine disorder conditions.
with a reported prevalence ranging from 4% Infertility or subfertility is a frequent
to 18% among women of reproductive age.1,2 concern among individuals diagnosed with
Several diagnostic criteria have been estab- PCOS with a reported prevalence varying
lished for the diagnosis of PCOS which are widely. Infertility is defined as the failure to
Correspondence: Saioa Torrealday, MD, 8901 Rock-
achieve a clinical pregnancy after 12 months
ville Pike, Bethesda, MD. E-mail: saioa.torrealday. or more of regular sexual intercourse in
mil@mail.mil women 35 years of age and below or after
The authors declare that they have nothing to disclose. 6 months or more in women above 35 years
CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 64 / NUMBER 1 / MARCH 2021
www.clinicalobgyn.com | 65
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.66 Lentscher et al
of age.3 While infertility affects nearly 12% The uncertainty surrounding fertility can
of couples worldwide, the American Society be particularly distressing for individuals with
of Reproductive Medicine (ASRM) esti- ties to communities with strong values and
mates the rate of infertility to be between ideals of fertility. While such data is limited, a
70% and 80% among individuals with study conducted in Vienna, Austria found
PCOS.4 Thus, ASRM recommends that an that Muslim immigrant women diagnosed
infertility evaluation in women with PCOS with PCOS who presented to a University
begin after 6 months of attempting to Clinic reported a much stronger desire for
conceive without success.4 According to the childrearing and more distress related to an
Centers for Disease Control (CDC), PCOS infertility diagnosis compared with European
is the most common cause of infertility women with PCOS.9 Thus, it is important to
owing primarily to the hallmark symptom of keep in mind that women with PCOS dealing
anovulation,5 however, several other fea- with infertility from various sociocultural
tures of PCOS are also thought to contribute backgrounds may have different psychosocial
to the inability to conceive, namely obesity pressures and needs.
and insulin resistance. This chapter will A prospective cohort study from 2016
provide an overview of the causes of infer- evaluated the QOL in 2 groups, 1 group con-
tility and will address fertility concerns sisted of females with PCOS and their
among women with PCOS. partners, while the other group was com-
prised of women with unexplained infertility
PSYCHOSOCIAL ASPECT OF and their partners. Using a validated assess-
FERTILITY CONCERNS ment, the fertility-specific QOL survey,
Infertility has profound implications for an women in each cohort were evaluated at
individual and their communities. Individuals baseline before initiation of fertility treatment.
most commonly report distress, depression, Women with PCOS had lower fertility-
anxiety, sexual dysfunction, lower self- specific QOL scores (72.3 ± 14.8) than those
esteem, and social discord following an with unexplained infertility (77.1 ± 12.8;
infertility diagnosis. This holds true for indi- P < 0.001); this trend held true for each
viduals diagnosed with PCOS. The uncer- domain (social, mind/body, emotional) eval-
tainty surrounding fertility is worrisome to uated in the study with the only exception
adolescents and women diagnosed with being in the relational domain.10 The authors
PCOS. In one study, girls with PCOS were suggest the differences in scores seen between
found to be 3.4 times more likely to be the 2 cohorts were largely explained by
worried about their ability to become preg- variation in body mass index (BMI), hirsut-
nant than the control group, and this concern ism, household income, and age.10 Further-
about future fertility was associated with more, the women in both groups had lower
significant reductions in quality of life scores than their male partners. This study
(QOL).6 Another study also demonstrated underscores that women with PCOS, partic-
that the potential for infertility has a negative ularly those with higher BMI, hirsutism, and
impact on the QOL among adolescent girls of lower socioeconomic class, may need
diagnosed with PCOS.7 Holton et al8 re- closer observation and when appropriate,
ported that these concerns arise out of offered mental health support given the
perception on the part of the individual with increased emotional and physical distress of
PCOS that it will be difficult for them to the condition.10
conceive, and thus there is a desire for
preconception counseling and evidence-based HYPOTHALAMIC-PITUITARY
educational materials so that patients can DYSREGULATION
make informed decisions surrounding their In PCOS women, there is a unique inter-
reproductive and sexual health. play between the hormones involved in the
www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.PCOS and Fertility 67
hypothalamic-pituitary axis that culminates OVARIAN DYSFUNCTION
in chronic anovulation and consequently The morphologic characteristics of PCOS
infertility. Unlike in normal cycling women consist of 2 main features: an increasing
who undergo hormonal variations through- number of antral follicles, and increase size
out the menstrual cycle in response to differ- and density of the ovarian stroma. While a
ent hormonal cues, women with PCOS have subset of women with these ovarian features
a relatively constant release of gonadotropins. are ovulatory, for many follicular growth
The invariable luteinizing hormone (LH) ceases once it reaches 5 to 8 mm in diameter.
pulse frequency in PCOS women mimics This failure to form a dominant follicle leads
the frequencies classically seen in the late to anovulation and subsequent infertility. The
follicular phase of normal ovulatory women; dense ovarian stroma is primarily composed
a pattern that favors LH over follicle-stim- of theca cells. The theca cells convert choles-
ulating hormone release.11 In PCOS women, terol to androgens through a succession
LH secreted by the anterior pituitary in of intermediary steps, with the primary
response to gonadotropin-releasing hormone output being androstenedione followed by
(GnRH) is characterized by increased pulse progesterone, 17alpha-hydroxyprogesterone,
frequency, and to a lesser degree also an and dehydroepiandrosterone.15 The andro-
increase in pulse amplitude.12 In addition, the gen overproduction by the theca cells in
LH receptors in PCOS women have a PCOS ovaries, as well as the hyperresponse
heightened response to GnRH when com- to LH provocation by these cells is one of the
pared with non-PCOS women.13 The abnor- key reasons for the hyperandrogenic ovarian
mal secretory dynamics described above are milieu in PCOS patients.
evident by the elevated serum LH levels and While androgens serve an important
high LH/follicle-stimulating hormone ratio physiological function in follicle develop-
classically seen in PCOS women. ment, hyperandrogenism has been shown
It is postulated that hyperandrogenism, in numerous animal studies to have an
which is a cornerstone of PCOS, may also aberrant effect on follicular development
increase GnRH pulse activity, leading to leading to negative effects on ovarian func-
both greater LH receptor sensitivity and tion. One study by Bertoldo et al16 found
elevated LH secretion.13 In an effort to see that isolated preantral and antral follicles
if the androgens impacted LH secretion, from PCOS mice resulted in slower growth
Eagleson et al14 treated women with PCOS compared with controls, and antral and
and a control group with progesterone either preovulatory PCOS follicles exhibited re-
alone or with estrogen (combination oral duced follicle health compared with controls.
contraception). Upon administration of the This study also found that PCOS female
hormone treatment, both groups had a mice showed a poorer response to hyper-
decrease in LH levels, however, it was more stimulation and impaired oocyte function.
pronounced in the control cohort. However, These findings led the authors to conclude
when women with PCOS who were treated that prolonged exposure to androgen excess
with the antiandrogen flutamide, following leads to aberrant follicle development, which
either progesterone or the combination of is persistent even after removal from that
oral contraception treatment, the women environment.16 Thus, although the exact
had restoration of LH levels similar to mechanism is unclear, ovarian dysregulation
normal controls.14 These findings corrobo- is also a contributor to infertility.
rate the notion that elevated androgens
inhibit the normal negative feedback of INSULIN RESISTANCE AND FERTILITY
estrogen and progesterone on LH pulse PCOS is commonly associated with insulin
release and play a role in normal hypothala- resistance and hyperinsulinemia; condi-
mic-pituitary function. tions which are thought to contribute to
www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.68 Lentscher et al
the pathogenesis of PCOS. In addition, epithelial cells, placenta, and in the pituitary
increased serum insulin levels and insulin gland.2 In addition, the placenta, endome-
resistance have been reported to be associated trium, and ovary also express 1α-hydroxy-
with decreased cycle ovulation, conception, lase, the enzyme required to synthesize
pregnancy, and live birth rates.17 In a 2012 1,25-dihydroxyvitamin D3 or calcitriol the
study of 45 reproductive-aged women with active form of vitamin D.2 In the endometrial
PCOS and 161 control women, Tsai et al18 stroma cells, calcitriol regulates expression of
amassed dietary intake, glucose metabolism, the HOXA10 gene, which is important for
and sex hormones for each group. Women successful implantation.21 Upregulation of
with PCOS had elevated postprandial glucose HOXA10 in the endometrium is necessary
levels, fasting insulin, and insulin resistance for embryo implantation. Cermik et al22
compared with women without PCOS, dem- demonstrate HOXA10 expression was re-
onstrated by marked metabolic profile differ- pressed by testosterone in women with
ences among the PCOS cohort.18 PCOS. Endometrial biopsies obtained from
Metformin is a biguanide insulin- women with PCOS demonstrated decreased
sensitizing agent that is often administered HOXA10 mRNA expression levels, indicat-
for PCOS women with clinical signs or ing a role for testosterone as a regulator of
biochemical evidence of insulin resistance, HOXA10 expression. Diminished uterine
with a goal of improving insulin resistance HOXA10 expression may also contribute to
and correcting the underlying hormonal the diminished reproduction potential of
disruption. Metformin has been proven to women with PCOS by limiting embryo
be particularly effective in reducing insulin implantation.22
resistance and improving ovulatory per- The vitamin D pathway has been sug-
formance. New insulin-sensitizing agents gested to have a regulatory role in PCOS-
are being used in women with PCOS to associated symptoms. Calcitriol has been
maximize positive effect on insulin while associated with follicular growth and deve-
limiting adverse side effects,19 as metformin lopment,23 and it has also been shown to
is poorly tolerated by some women due to increase the expression of the insulin receptor,
gastrointestinal distress. Metformin also has insulin synthesis and secretion, and insulin
been shown to increase ovulation when sensitivity.21 The presence of vitamin D
compared with placebo, however, it is less receptor polymorphisms have been shown
effective than other oral ovulation-induction to be associated with the severity of PCOS
agents; thus, metformin should not be uti- phenotype; although these findings are con-
lized as a first-line treatment for this troversial and need further investigation.
indication.20 The different medications for While lower vitamin D levels have been
ovulation induction are discussed in greater associated with ovulatory and menstrual
detail in the pharmacotherapy chapter. irregularities, lower pregnancy success,
hirsutism, hyperandrogenism, obesity, and
VITAMIN D DEFICIENCY AND elevated cardiovascular disease risk factor,24
FERTILITY the prevalence of vitamin D deficiency
Vitamin D has traditionally been associ- among individuals with PCOS is also con-
ated primarily with bone function and troversial. Two different meta-analyses re-
calcium and phosphorus homeostasis, ported that women with PCOS had
however, expression of the vitamin D substantially lower levels of vitamin D, yet
receptor in the ovaries, uterus, and pla- noted that vitamin D deficiency was more
centa have suggested a role for vitamin D common in a patient in PCOS women who
in reproduction. The vitamin D receptor are obese compared with nonobese PCOS
is expressed in granulosa cells, cumulus women.25,26 Importantly, a meta-analysis
oophorus cells, endometrium, fallopian by He et al27 did not show significant
www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.PCOS and Fertility 69
improvement in markers of insulin resistance inflammation is quite difficult. Oxidative
nor hyperandrogenism with vitamin D sup- stress is positively correlated with androgen
plementation among individuals with PCOS. levels and contributes to hyperandrogenism
Thus, the increased risk of vitamin D defi- in PCOS patients. Follicular fluid is complex
ciency among women with PCOS may be and contains a mixture of protein, sugar,
related to associated comorbidities, and not reactive oxygen species, antioxidants, and
necessarily to the pathophysiology of PCOS hormones.32 Oocytes have a large quantity
itself. of mitochondria that play an important
regulatory role in oocyte maturation, fertil-
FERTILITY AND MITOCHONDRIA ization, and preimplantation embryo
FUNCTION development.32 The concentration of these
The relationship of cellular dysfunction and substances directly affects oocyte maturity
PCOS has garnered attention in a recent and quality. Imbalances between antioxidant
investigation, with mitochondria thought to factors and reactive oxygen species in the
play a large role to the underlying etiology. follicular fluid may have adverse effects on
Mitochondria are the functional “power- oocyte quality, fertilization, and embryo
house” of the cell and play a fundamental development. This process is likely through
role in cell energy metabolism and apoptosis, alteration of the equilibrium of the follicular
as well as signal transduction for cell microenvironment and results in abnormal
proliferation.28 The role of mitochondrial ovulation and infertility in patients with
function disorders in the pathogenesis of PCOS.33 Numerous indicators of oxidative
PCOS has been demonstrated by Papalou stress are abnormal in the blood and follicular
et al.29 It may account for several character- fluid of patients with PCOS and may play a
istics of PCOS, such as androgen excess, role in infertility among these women.
insulin resistance, obesity, abnormal follicu-
lar development, and inflammation. FERTILITY AND OBESITY
While the exact relationship between In the United States, nearly 50% of repro-
mitochondrial dysfunction and PCOS is ductive age women are overweight (BMI >
unknown, there are several factors that are 25 kg/m2) or obese (BMI > 30 kg/m2).34 Obe-
thought to contribute to the disruption.30 sity alone is a risk factor for hypertension,
Replication errors are more likely to occur dyslipidemia, DM, sleep apnea, and cardio-
in mitochondrial DNA than in nuclear vascular disease; thus, elevating the rate of all-
DNA, which leads to greater mutations, cause mortality in this population.35 Women
deletions, and mitochondrial DNA molecule with PCOS, who manifest the overweight or
depletion. In addition, oxidative stress- obese phenotype, can suffer not only from
induced cellular damage is increased in wom- these negative health implications but also
en with PCOS, and although the exact from infertility. Obesity is commonly associ-
mechanism is unknown, it is thought to lead ated with ovulatory dysfunction; women with
to insulin resistance and other metabolic a BMI > 27 kg/m2 have a relative risk (RR)
abnormalities, the possibility at the level of of anovulatory infertility of 3.1 [95% con-
the mitochondria. This pathway may also be fidence interval (CI), 2.2-4.4] compared with
responsible for cellular changes which lead to their lean counterparts.36,37 Furthermore,
the development of metabolic syndrome; a obesity is associated with higher doses of
condition often seen in PCOS women char- medication to induce ovulation as well as a
acterized by hypertension, increased abdomi- decreased response to clomiphene citrate
nal adiposity, dyslipidemia, and impaired [increased BMI: odds ratio (OR): 0.92; 95%
glucose metabolism.31 Cellular oxidative CI, 0.40-0.89].38 Moreover, in a systematic
stress is closely related to inflammation, and review of 27 in vitro fertilization (IVF) studies
the ability to completely distinguish it from showed that women with obesity have
www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.70 Lentscher et al a reduced chance of clinical pregnancy and pregnancy. Thus, a stepwise approach to live birth compared with normal-weight treatment should be formulated for women women.39 This was confirmed in a meta- with PCOS, with strong consideration on analysis of 33 IVF studies of over 47,000 treatment modality based on the risk/bene- cycles which concluded that overweight and fit stratification. The different infertility obese women have a significantly reduced treatments are discussed in more detail in rates of clinical pregnancy (RR: 0.90, other chapters. P < 0.0001) and live birth (RR: 0.84, P = 0.0002) compared with women with a PCOS AND PREGNANCY BMI of
PCOS and Fertility 71
pregnant women with a BMI > 25 kg/m2 cause of maternal mortality.51 This category
and with PCOS, acanthosis nigricans, or any encompasses various conditions to include
other condition associated with insulin resist- chronic hypertension, gestational hyperten-
ance should be screened early in pregnancy sion, preeclampsia/eclampsia as well as
given the high risk for type 2 DM.45 chronic hypertension with superimposed pre-
While there are similar metabolic risks, eclampsia. The different hypertensive disor-
it is still unclear if PCOS independently ders are characterized by the onset of
increases the risk of GDM, or if this is hypertension (either prepregnancy, before
related to increased adiposity. Mikola 20 wk gestation, or after 20 wk gestation),
et al46 found that PCOS independently presence or absence of proteinuria, the oc-
increased the risk of GDM, but that currence of end-organ dysfunction, or seiz-
overweight or obese women with PCOS ures. Given that some of the risk factors for
was the strongest predictor for the devel- hypertensive disorders are also associated
opment of GDM. Similarly, in a meta- with PCOS, namely diabetes and obesity,
analysis of 15 studies, Boomsma et al43 the association between the 2 conditions
found women with PCOS demonstrated a seems plausible.
significantly higher change of developing A pooled meta-analysis of 15 studies
GDM compared with controls (OR: 2.94; showed that women with PCOS demon-
95% CI, 1.70-4.08). Furthermore, a sub- strated a significantly higher chance of devel-
group analysis of 5 higher validity studies oping a hypertensive disorder of pregnancy
from Boomsma et al’s43 meta-analysis when compared with non-PCOS women
further reinforced the increased risk of (OR: 3.67; 95% CI, 1.98-6.81).43 Similarly,
PCOS women developing GDM (OR: women with PCOS also demonstrated a
3.66; 95% CI, 1.20-11.16). In a more significantly higher probability of developing
recent meta-analysis investigating 29 preeclampsia than the control cohort (OR:
studies, PCOS in pregnancy was again 3.47; 95% CI, 1.95-6.17).43 It should be noted
associated with a significantly increased that in all studies in which preeclampsia was
risk of GDM when compared with non- an endpoint there was reported a lower
PCOS women (RR: 2.78; 95% CI, 2.27- parity, higher BMI, and more multiple ges-
3.40).47 Conversely, a large multicenter tations among women with PCOS versus
case-control study of over 2000 women controls. Yu et al47 in a meta-analysis of 29
indicated that the increased risk of GDM studies that evaluated preeclampsia and ges-
in women with PCOS was related to tation hypertension between PCOS pregnan-
obesity and maternal age rather than the cies versus pregnancies without PCOS
underlying PCOS diagnosis.48 Similarly, showed a harmful impact for both conditions
2 case-control studies evaluating PCOS (preeclampsia: RR: 2.79; 95% CI, 2.29-3.38,
women with non-PCOS women, who gestational hypertension: RR: 2.46; 95% CI,
were matched by BMI and age, showed 1.95-3.09) in PCOS women. Given the higher
no increase in GDM within the PCOS likelihood for hypertensive disorders in preg-
cohort.49,50 Since there are different nancy among women with PCOS, careful
PCOS phenotypes, screening for GDM attention to blood pressure and symptoma-
should be underscored in those women tology at each prenatal visit and postpartum
with risk factors and an increased BMI as should be undertaken.
per the current recommendations.
Alteration in Birth Weight
Hypertensive Disorders in Pregnancy As previously highlighted, there is an
Hypertensive disorders in pregnancy are increased risk of both DM and hypertensive
estimated to affect 6% to 8% of all pregnancy disorders in PCOS women. Ironically,
in the United States and is the second leading women with DM are at increased risks of
www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.72 Lentscher et al
macrosomia, whereas those women with opposed this claim or suggested this obser-
hypertensive disorders have an increased vation may be dose dependent or based on
chance of small for gestational age (SGA) early pregnancy monitoring/testing in this
infants secondary to placental insufficiency. subgroup.55
In a pooled meta-analysis of 12 studies, the An increase in early pregnancy loss has
data revealed a statistically, albeit not also been attributed to the increased
clinically, significant lower neonatal birth prevalence of elevated LH levels, hyper-
weight among infants of women with androgenism, insulin resistance, and obe-
PCOS (mean weight difference: −38.4 g; sity. Though elevated LH levels have been
95% CI, −62.2 to −14.6).43 However, when associated with an increased risk of mis-
a subgroup analysis of 4 studies in which carriage, this has not been found to be
controls were matched for confounders predictive of pregnancy loss.56 Insulin
there was no significant difference in birth resistance, however, has been identified
weight. Similarly, in a meta-analysis per- as an independent risk factor for miscar-
taining to the outcomes of macrosomia (11 riage, particularly when not controlled.57
studies) and SGA infants (10 studies) in One study by Wang et al58 showed that
women with PCOS compared with con- although women with PCOS were found
trols, the data showed that pregnant PCOS to have an increase in the prevalence of
women did not have an increased risk of spontaneous abortion compared with
macrosomia (RR: 1.14; 95% CI, 0.96-2.20) women without PCOS, this effect was
or SGA (RR: 1.45; 95% CI, 0.96-2.20).47 decreased to nonsignificant and ulti-
Thus, an underlying PCOS diagnosis does mately nil after controlling for obesity
not appear to play a role in the birth weight and other confounding factors including
of the infant. the type of treatment received. Thus, the
increased rate of miscarriage seen among
Early Pregnancy Loss women with PCOS may be secondary to
Spontaneous abortion in women with the increased prevalence of obesity, insu-
PCOS has been reported to be as high as lin resistance, and other confounding
30% to 40%, which is ∼3-fold higher than the factors.
reported rates of 10% to 15% for women
without PCOS.52 Similarly, individuals with
recurrent miscarriage have been found to Conclusions
have a higher prevalence of polycystic-ap- Women with PCOS are at increased risk for
pearing ovaries on ultrasound (40% to 82%), infertility owing primarily to anovulation.
compared with those unaffected (23%).53 It However, given the various hormonal per-
should be noted, however, that these studies turbations experienced by women with
often use nonstandardized diagnostic criteria PCOS, several factors likely play a critical
and varying imagine modalities to assess the role in fertility as addressed in this chapter.
ovarian findings. One possible explanation While there is still much to glean about the
for the observed increase in the spontaneous relationship between PCOS and fertility, it is
abortion rate among women with PCOS is clear that lifestyle modifications, weight
the use of ovulation-induction agents includ- optimization, and when indicated, medica-
ing the use of clomiphene citrate. A signifi- tion may be beneficial. The goal in treating
cantly higher rate of spontaneous abortion PCOS women is to optimize their health
has been reported among pregnancies result- preconceptionally in efforts to achieve a
ing from the use of clomiphene citrate successful pregnancy while minimizing ob-
compared with spontaneous pregnancies in stetric complications. Women with PCOS
patients who are otherwise experiencing should be encouraged that they can success-
subfertility.54 However, other studies have fully conceive and have a healthy pregnancy.
www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.PCOS and Fertility 73
However, more research is still needed to clinically defined women with polycystic ovarian
better understand the relationship between syndrome. J Clin Endocrinol Metab. 1997;82:
PCOS and fertility so that women with 2248–2256.
13. Morales AJ, Laughlin GA, Butzow T, et al.
PCOS can be appropriately counsel and Insulin, somatotropic and luteinizing hormone
aided when they seek medical attention. axes in lean and obese women with polycystic
ovarian syndrome: common and distinct features.
J Clin Endocrinol Metab. 1996;81:2854–2864.
14. Eagleson CA, Gingrich MB, Pastor CL, et al.
References Polycystic ovarian syndrome: evidence that fluta-
1. Melo AS, Vieira CS, Barbieri MA, et al. High mide restores sensitivity of the gonadotropin-
prevalence of polycystic ovary syndrome in wom- releasing hormone pulse generator to inhibition
en born small for gestational age. Hum Reprod. by estradiol and progesterone. Clin Endocrinol
2010;25:2124–2131. Metab. 2000;85:4047–4052.
2. Muscogiuri G, Altieri B, de Angelis C, et al. 15. Gilling-Smith C, Willis DS, Beard RW, et al.
Shedding new light on female fertility: the role of Hypersecretion of androstenedione by isolated
vitamin D. Rev Endocr Metab Disord. 2017;18: theca cells from polycystic ovaries. J Clin Endo-
273–283. crinol Metab. 1994;79:1158–1165.
3. World Health Organization (WHO). Infertility 16. Bertoldo MJ, Caldwell ASL, Riepsamen AH,
Definitions and Terminology. Geneva, Switzer- et al. A hyperandrogenic environment causes
land: World Health Organization, World Health intrinsic defects that are detrimental to follicular
Organization; 2016. dynamics in a PCOS mouse model. Endocrinol-
4. Practice Committee of the American Society for ogy. 2019;160:699–715.
Reproductive Medicine. Definitions of infertility 17. Zhang D, Yang X, Li J, et al. Effect of hyper-
and recurrent pregnancy loss: a committee opin- insulinemia and insulin resistance on endocrine,
ion. Fertil Steril. 2013;99:63. metabolic and fertility outcomes in women with
5. Centers for Disease Control and Prevention. Infer- polycystic ovary syndrome undergoing ovulation
tility FAQs, CTRS. 2019. Available at: www.cdc. induction. Clin Endocrinol (Oxf). 2019;91:
gov/reproductivehealth/infertility/. Accessed January 440–448.
2019. 18. Tsai YH, Wang TW, Wei HJ, et al. Dietary
6. Trent ME, Rich M, Austin SB, et al. Fertility intake, glucose metabolism and sex hormones in
concerns and sexual behavior in adolescent girls women with polycystic ovary syndrome (PCOS)
with polycystic ovary syndrome: implications for compared with women with non-PCOS-related
quality of life. J Pediatr Adolesc Gynecol. 2003;16: infertility. Br J Nutr. 2013;109:2190–2198.
33–37. 19. Morgante G, Massaro MG, Di Sabatino A, et al.
7. Jones GL, Hall JM, Lashen HL, et al. Health- Therapeutic approach for metabolic disorders
related quality of life among adolescents with and infertility in women with PCOS. Gynecol
polycystic ovary syndrome. J Obstet Gynecol Endocrinol. 2018;34:4–9.
Neonatal Nurs. 2011;40:577–588. 20. Practice Committee of the American Society for
8. Holton S, Hammarberg K, Johnson L. Fertility Reproductive Medicine. Role of metformin for
concerns and related information needs and pref- ovulation induction in infertile patients with
erences of women with PCOS. Hum Reprod Open. polycystic ovary syndrome (PCOS): a guideline.
2018;2018:hoy019. Fertil Steril. 2017;108:426–441.
9. Schmid J, Kirchengast S, Vytiska-Binstorfer E, et al. 21. Du H, Daftary GS, Lalwani SI, et al. Direct
Psychosocial and sociocultural aspects of infertility—a regulation of HOXA10 by 1,25-(OH)2D3 in
comparison between Austrian women and immigrant human myelomonocytic cells and human endo-
women. Anthropol Anz. 2004;62:301–309. metrial stromal cells. Mol Endocrinol. 2005;19:
10. Santoro N, Eisenberg E, Trussell JC, et al. Fer- 2222–2233.
tility-related quality of life from two RTC cohorts 22. Cermik D, Selam B, Taylor HS. Regulation of
with infertility: unexplained infertility and poly- HOXA-10 expression by testosterone in vitro and
cystic ovary syndrome. Hum Reprod. 2016;31: in the endometrium of patients with polycystic
2268–2279. ovary syndrome. J Clin Endocrinol Metab. 2003;88:
11. Waldstreicher J, Santoro NF, Hall JE, et al. 238–243.
Hyperfunction of the hypothalamic-pituitary axis 23. Chang HM, Klausen C, Leung PC. Antimullerian
in women with PCOS. J Clin Endocrinol Metab. hormone inhibits follicle-stimulating hormone-in-
1988;66:165–172. duced adenylyl cyclase activation, aromatase expres-
12. Taylor AE, McCourt B, Martin KA, et al. Deter- sion, and estradiol production in human granulosa-
minants of abnormal gonadotropin secretion in lutein cells. Fertil Steril. 2013;100:585–592.
www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.74 Lentscher et al
24. Thomson RL, Spedding S, Buckley JD. Vitamin reproductive technologies in overweight and
D in the aetiology and management of polycystic obese women. Hum Reprod. 2012;27:457–467.
ovary syndrome. Clin Endocrinol (Oxf). 2012;77: 40. Rittenberg V, Seshadri S, Sunkara SK, et al.
343–350. Effect of body mass index on IVF treatment
25. Jia XZ, Wang YM, Zhang N, et al. Effect of vitamin outcome: an updated systematic review and
D on clinical and biochemical parameters in poly- meta-analysis. Reprod Biomed Online. 2011;23:
cystic ovary syndrome women: a meta-analysis. 421–439.
J Obstet Gynaecol Res. 2015;41:1791–1802. 41. Kjerulff LE, Sanchez-Ramos L, Duffy D. Preg-
26. Tsakova AD, Gateva AT, Kamenov ZA. 25(OH) nancy outcomes in women with polycystic ovary
vitamin D levels in premenopausal women with syndrome: a meta-analysis. Am J Obstet Gynecol.
polycystic ovary syndrome and/or obesity. Int J 2011;204:558.e1–558.e6.
Vitam Nutr Res. 2012;82:399–404. 42. Qin JZ, Pang LH, Li MJ, et al. Obstetric
27. He C, Lin Z, Robb SW, et al. Serum vitamin D complications in women with polycystic ovary
levels and polycystic ovary syndrome: a system- syndrome: a systematic review and meta-analysis.
atic review and meta-analysis. Nutrients. 2015;7: Reprod Biol Endocrinol. 2013;11:56.
4555–4577. 43. Boomsma CM, Eijkemans MJC, Hughes EG,
28. Wallace DC. Mitochondria as chi. Genetics. 2008; et al. A meta-analysis of pregnancy outcomes in
179:727–735. women with polycystic ovary syndrome. Hum
29. Papalou O, Victor VM, Diamanti-Kandarakis E. Reprod Update. 2006;12:673–683.
Oxidative stress in polycystic ovary syndrome. 44. Moore TR, Catalano P. Diabetes in pregnancy.
Curr Pharm Des. 2016;22:2709–2722. In: Creasy RK, Resnick R, Iams JD, eds. Creasy
30. Zhang J, Bao Y, Zhou X, et al. Polycystic ovary and Resnik’s Maternal-Fetal Medicine: Principles
syndrome and mitochondrial dysfunction. Reprod and Practice, 6th ed. Philadelphia, PA: Saunders
Biol Endocrinol. 2019;17:67. Elsevier; 2009:953–994.
31. Mahalingaiah S, Diamanti-Kandarakis E. Tar- 45. Committee on Practice Bulletins—Obstetrics.
gets to treat metabolic syndrome in polycystic ACOG Practice Bulletin No. 190: Gestational
ovary syndrome. Expert Opin Ther Targets. 2015;19: diabetes mellitus. Obstet Gynecol. 2018;131:
1561–1574. e49–e64.
32. Chappel S. The role of mitochondria from mature 46. Mikola M, Hiilesmaa V, Halttunen M, et al. Obstetric
oocyte to viable blastocyst. Obstet Gynecol Int. outcome in women with polycystic ovarian syndrome.
2013;2013:183024. Hum Reprod. 2001;16:226–229.
33. Nuñez-Calonge R, Cortés S, Gutierrez Gonzalez 47. Yu H, Chen H, Rao D, et al. Association between
LM, et al. Oxidative stress in follicular fluid of polycystic ovary syndrome and the risk of preg-
young women with low response compared with nancy complications: a PRISMA—compliant
fertile oocyte donors. Reprod Biomed Online. systematic review and meta-analysis. Medicine
2016;32:446–456. (Baltimore). 2016;95:e4863.
34. Flegal KM, Carroll MD, Kit BK, et al. Preva- 48. Mustaniemi S, Vaarasmaki M, Eriksson JG, et al.
lence of obesity and trends in the distribution of Polycystic ovary syndrome and risk factors for
body mass index among US adults, 1999-2010. gestational diabetes. Endocr Connect. 2018;7:
JAMA. 2012;307:491–497. 859–869.
35. Practice Committee of the American Society for 49. Haakova L, Cibula D, Rezabek K, et al. Preg-
Reproductive Medicine. Obesity and reproduc- nancy outcomes in women with PCOS and in
tion: a committee opinion. Fertil Steril. 2015;104: controls matched by age and weight. Hum Re-
1116–1125. prod. 2003;18:1438–1441.
36. Rich-Edwards JW, Goldman MB, Willett WC, 50. Turhan NO, Seckin NC, Aybar F, et al. Assessment
et al. Adolescent body mass index and infertility of glucose tolerance and pregnancy outcome of
caused by ovulatory disorder. Am J Obstet Gyne- polycystic ovary patients. Int J Gynaecol Obstet.
col. 1994;171:171–177. 2003;81:163–168.
37. Grodstein F, Goldman MB, Cramer DW. Body 51. ACOG Practice Bulletin No. 202: Gestational
mass index and ovulatory infertility. Epidemiol- hypertension and preeclampsia. Obstet Gynecol. 2019;
ogy. 1994;5:247–250. 133:e1–e25.
38. Imani B, Eijkemans MJ, te Velde ER, et al. A 52. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al.
nomogram to predict the probability of a live Effects of metformin on early pregnancy loss in
birth after clomiphene citrate induction of ovula- polycystic ovary syndrome. J Clin Endocrinol Metab.
tion in normogondotropic oligoamenorrheic in- 2002;87:524–529.
fertility. Fertil Steril. 2002;77:91–97. 53. Sagle M, Bishop K, Ridley N, et al. Recurrent
39. Konic AM, Mutsaerts MA, Kuchenbecker WK, early miscarriage and polycystic ovaries. BMJ.
et al. Complications and outcome of assisted 1988;297:1027–1028.
www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.PCOS and Fertility 75
54. Dickey RP, Taylor SN, Curole DN, et al. In- normogonadotrophic anovulatory infertility. Re-
cidence of spontaneous abortion in clomiphene prod Biomed Online. 2003;7:170–178.
pregnancies. Hum Reprod. 1996;11:2623–2628. 57. Tian L, Shen H, Lu Q, et al. Insulin resistance
55. Boomsma CM, Fauser BC, Macklon NS. Preg- increases the risk of spontaneous abortion after
nancy complications in women with polycystic assisted reproduction technology treatment.
ovary syndrome. Semin Reprod Med. 2008;26: J Clin Endocrinol Metab. 2007;92:1430–1433.
72–84. 58. Wang JX, Davies MJ, Norman RJ. Polycystic
56. Mulders AG, Eijkman’s MJ, Imani B, et al. ovarian syndrome and the risk of spontaneous
Prediction of chances for success or complic- abortion following assisted reproductive technol-
ations in gonadotrophin ovulation induction in ogy treatment. Hum Reprod. 2001;16:2606–2609.
www.clinicalobgyn.com
Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved.You can also read
