Polycystic ovarian syndrome and low milk supply: Is insulin resistance the missing link?

Abstract

Despite the known maternal and infant benefits of breastfeeding, only about two-fifths of infants are exclusively breastfed for the first 6 months of life, with low milk supply among the most commonly cited reasons for breastfeeding cessation. Although anecdotal reports from lactation consultants indicate that polycystic ovarian syndrome (PCOS) interferes with lactation, very few studies have examined this relationship, and the association between PCOS and lactation dysfunction remains poorly understood. Moreover, studies have reported conflicting results when examining breastfeeding success in women with PCOS, and divergence of the PCOS phenotype may be responsible for the heterogeneous results to date. Specifically, insulin resistance may have an aggravating or even essential role in the pathogenesis of low milk supply. Recently, protein tyrosine phosphatase, receptor type, F has been identified as a potential biomarker linking insulin resistance with insufficient milk supply. Accordingly, interventions targeting insulin action have been recognized as potentially promising strategies toward the treatment of lactation dysfunction. This review will highlight studies linking PCOS with low milk supply and explore potential mechanisms that contribute to lactation dysfunction in these women.

Full text

Kirigin Biloš et al.
PB Endocr Oncol Metab 2017; Volume 3, Issue 2 49Endocr Oncol Metab 2017; Volume 3, Issue 2
REVIEW
Polycystic ovarian syndrome and low milk
supply: Is insulin resistance the missing link?
Lora Stanka Kirigin Biloš
Department of Endocrinology, Diabetes and Metabolic Diseases “Mladen Sekso”, University Hospital Center “Sestre Milosrdnice”, University of Zagreb Medical
School, Vinogradska Cesta 29, 10000 Zagreb, Croatia
Abstract
Despite the known maternal and infant benets of breastfeeding, only
about two-hs of infants are exclusively breastfed for the rst 6months
of life, with low milk supply among the most commonly cited reasons
for breastfeeding cessation. Although anecdotal reports from lactation
consultants indicate that polycystic ovarian syndrome (PCOS) interferes
with lactation, very few studies have examined this relationship, and the
association between PCOS and lactation dysfunction remains poorly
understood. Moreover, studies have reported conicting results when
examining breastfeeding success in women with PCOS, and divergence
of the PCOS phenotype may be responsible for the heterogeneous
results to date. Specically, insulin resistance may have an aggravating
or even essential role in the pathogenesis of low milk supply. Recently,
protein tyrosine phosphatase, receptor type, F has been identied as a
potential biomarker linking insulin resistance with insucient milk supply.
Accordingly, interventions targeting insulin action have been recognized
as potentially promising strategies toward the treatment of lactation
dysfunction. This review will highlight studies linking PCOS with low milk
supply and explore potential mechanisms that contribute to lactation
dysfunction in these women.
Key words: Insulin resistance; lactation; low milk supply; polycystic ovarian
syndrome
Corresponding author:
Lora Stanka Kirigin Biloš, Department of
Endocrinology, Diabetes and Metabolic
Diseases “Mladen Sekso”, University
Hospital Center “Sestre Milosrdnice”,
University of Zagreb Medical School,
Zagreb, Croatia, Phone: +91-919326983,
e-mail: lora.s.kirigin@gmail.com
DOI: 10.21040/eom/2017.3.2.3
Received: May 06th2017
Accepted: June 14th2017
Published: June 30th2017
Copyright: © Copyright by Association
for Endocrine Oncology and Metabolism.
This is an Open Access article distributed
under the terms of the Creative
Commons Attribution Non-Commercial
License (http://creativecommons.org/
licenses/by-nc/4.0/) which permits
unrestricted non-commercial use,
distribution, and reproduction in any
medium, provided the original work is
properly cited.
Funding: None.
Conict of interest statement: The
author declares that she has no conict
of interest.
Data Availability Statement: All
relevant data are within the paper.

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50 Endocr Oncol Metab 2017; Volume 3, Issue 2 51Endocr Oncol Metab 2017; Volume 3, Issue 2
1. Introduction
Breastfeeding provides many benets to both mother and
child, which is why the World Health Organization (WHO)
and the American Academy of Pediatrics recommend
exclusive breastfeeding for the first 6months of life
with continued breastfeeding until at least 1year[1,2].
However, only about two-hs of infants worldwide are
exclusively breastfed for the rst 6months of life[3],
with low milk supply accounting for the majority of
breastfeeding cessation [4,5].
Polycystic ovarian syndrome (PCOS) is characterized
by chronic anovulation, hyperandrogenism, and
polycystic ovarian morphology [6]. e cause of PCOS
is multifactorial and not fully understood, with a
combination of genetic and environmental factors the
likely culprit [7]. Several hormonal alterations are found in
women with PCOS including ovarian hyperandrogenism
and insulin-resistant hyperinsulinism.
Breastfeeding involves a complex interplay of several
hormones, many of which are disordered in women with
PCOS, and these hormonal alterations may interfere
with mammogenesis, lactogenesis, or galactopoiesis [8].
Anecdotal reports from lactation consultants indicate
that PCOS interferes with lactation; however, very few
studies have examined this relationship. is is surprising
considering the high prevalence of PCOS among women
of childbearing age [9] and the known benefits of
breastfeeding [10]. Furthermore, due to advances in
reproductive technology, more and more women with
PCOS have successful pregnancies, with little known
about the eect, it will have on lactation.
Studies have reported conflicting results when
examining breastfeeding success in women with PCOS
(Table 1) [11,12], and the contribution of PCOS to
lactation diculties remains poorly understood. e
rst study to suggest a potential link between PCOS and
low milk supply was a case report that described three
women with PCOS who failed to breastfeed [8]. Later,
in a case-control study, Vanky et al. reported somewhat
reduced breastfeeding rates in women with PCOS in the
early postpartum period [11].
Insulin resistance and obesity are negatively associated
with lactation [13-15], and because women with PCOS
have an increased risk for both obesity and insulin
resistance[6,16], this may contribute to their lactation
diculties. In addition, hyperandrogenism, as well as
alterations in estrogen, progesterone, and prolactin
metabolism may also be involved in the pathogenesis [17].
Although the association and mechanism behind PCOS
and low milk supply still need to be elucidated, clinicians
should be aware of this potential complication, as early
breastfeeding counseling and follow-up care with a
qualied lactation professional can help these women
reach their breastfeeding goals. Furthermore, identifying
high-risk patients will ensure that any correctable causes
of insucient milk supply are corrected without adversely
aecting infant nutrition [8].
2. Hormones Involved in Mammary Gland
Development
Estrogen and progesterone stimulate breast development
throughout puberty and pregnancy [17]. During puberty, a
rise in circulating estrogen stimulates ductal growth. Early
in pregnancy, progesterone and prolactin facilitate alveolar
growth. Secretory dierentiation or lactogenesis I occurs
during midpregnancy and results in mammary epithelial
cell dierentiation. Later, the fall in progesterone aer
parturition results in secretory activation or lactogenesis
II, stimulating milk secretion [8,17].
Women with PCOS have decreased levels of progesterone,
which could potentially interfere with alveolar growth during
pregnancy [8]. Furthermore, despite high circulating levels
of estrogen in women with PCOS, hyperandrogenism may
downregulate estrogen and prolactin receptors [8]. Insulin
and glucocorticoids are also essential for lactogenesis to
occur, but their signaling pathways and downstream targets
are not completely understood [17].
3. Low Milk Supply and the Hyperinsulinemia-
Androgen Connection
Androgens inhibit lactation [18] and are elevated in pregnant
women with PCOS [19]. e rst study to report an association
between androgens and breastfeeding outcomes in women

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with PCOS was a case-control study that included 36 women
with PCOS and 99 controls [11]. e researches found that
third-trimester dehydroepiandrosterone (DHEAS) levels
were negatively correlated with breastfeeding rates at 1-and
3-month postpartum. However, in a later follow-up study of
a randomized controlled trial (RCT) of metformin versus
placebo in women with PCOS (the PregMet study [20]),
DHEAS, testosterone, and free testosterone index had no
impact on breastfeeding [21].
Insulin resistance, followed by compensatory
hyperinsulinemia, is frequently found in patients with
Table 1: Main findings published in the literature concerning the relationship between PCOS and
breastfeeding success
Study title Year
published
Reference # Study design Study description Main results and
conclusions
Pregnancy outcome
in infertile patients
with polycystic ovary
syndrome who were
treated with metformin
2006 [12] Single‑center
retrospective case
analysis
To analyze pregnancy
health parameters and
outcomes (including
breastfeeding success)
in patients with PCOS
treated with metformin
Breastfeeding success was
not affected by PCOS or
metformin use
Of the women that
attempted breastfeeding,
78% (97/124) were
successful and 22% failed
Only four women attributed
poor milk production as
a reason for stopping
breastfeeding
Breastfeeding in
polycystic ovary
syndrome
2008 [11] Case‑control
study
To investigate the
breastfeeding rate
in new mothers with
PCOS at 1‑, 3‑, and
6‑month postpartum
Androgen levels were
analyzed and related to
breastfeeding rate
Women with PCOS
had a somewhat lower
breastfeeding rate at
1‑month postpartum in
comparison to controls
Breastfeeding rates were
equal at 3‑ and 6‑month
postpartum
DHEAS at gestational week
32 and 36 showed a weak
negative association with
breastfeeding in PCOS
women
Breast size increment
during pregnancy
and breastfeeding in
mothers with polycystic
ovary syndrome:
A follow‑up study of a
randomized controlled
trial on metformin
versus placebo
2012 [21] Follow‑up study
of a randomized
controlled trial (the
PregMet study)
Metformin versus
Placebo
To study the
significance of breast
size increment in
pregnancy and the
impact of metformin
during pregnancy on
breastfeeding in women
with PCOS
Neither metformin nor
androgens had any impact
on breast size increment in
pregnancy or breastfeeding
Women with PCOS that
did not have breast size
increment during pregnancy
were more metabolically
disturbed (obese, higher
BP, serum triglycerides, and
fasting insulin levels) and
breastfeed less than those
with breast size increment
BMI correlated negatively
with duration of partial
breastfeeding
PCOS: Polycystic ovarian syndrome, DHEAS: Dehydroepiandrosterone sulfate, BMI: Body mass index, BP: Blood pressure

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52 Endocr Oncol Metab 2017; Volume 3, Issue 2 53Endocr Oncol Metab 2017; Volume 3, Issue 2
PCOS and is in part responsible for the increased
levels of androgens in these women [22]. is so-called
“hyperinsulinemia-androgen connection” is a vicious
cycle, whereby insulin directly induces excess androgen
production by theca cells [23] and decreases sex hormone-
binding globulin (SHBG) production by the liver [24].
is leads to more free androgens, which in turn interferes
with removal of insulin by the liver.
Approximately 30-40% of women with PCOS have
impaired glucose tolerance, and 10% develop Type 2
diabetes mellitus by the age of 40 [6,16]. e previous
studies have shown diabetes to be negatively associated
with lactation[13]. One study found that mothers with
gestational diabetes, especially mothers with insulin-
dependent gestational diabetes, and obese mothers
breastfed their children significantly less and for a
shorter duration than healthy mothers [25]. Gestational
diabetes has also been associated with delayed onset
of lactogenesis[26]. In a case-control analysis, women
diagnosed with low milk supply were signicantly more
likely to have had diabetes in pregnancy compared with
women with latch or nipple problems. An independent
effect of PCOS on the risk of low milk supply was
not observed in a model that included diabetes, and
the authors concluded that “PCOS as a risk factor for
insucient lactation may be limited to the subset of
women with postpartum glucose intolerance” [13].
e association between low milk supply and insulin
dysregulation was elegantly demonstrated in a recent
study that compared gene expression in the milk fat
globule transcriptome of women with or without low
milk supply [27]. Milk fat globules are a rich source
of mammary epithelial cell messenger RNA (mRNA),
and using RNA-sequencing technology, the researchers
found that protein tyrosine phosphatase, receptor type,
F (PTPRF), which blocks the action of insulin to stimulate
milk production, is overexpressed in the mammary gland
of women with low milk supply. erefore, PTPRF may
serve as a biomarker linking insulin resistance with
insucient milk supply. Women with decreased insulin
sensitivity might have a more sluggish increase in milk
output in response to infant demand as a result of PTPRF
overexpression in the mammary gland [27]. ese ndings
suggest that interventions targeting insulin action may be
a promising and novel strategy toward improving milk
supply in susceptible mothers [13].
Metformin could improve lactation through its favorable
eect on insulin resistance. However, in a retrospective
case analysis of pregnancy outcomes in 188 PCOS
patients treated with metformin, breastfeeding success
was not aected by PCOS or metformin use. Of the 124
women that attempted breastfeeding, 78% (97/124) were
successful, and 22% (27/124) failed [12]. Only four women
attributed poor milk production as a reason for stopping
breastfeeding. Furthermore, in a follow-up study of an
RCT of metformin versus placebo in pregnant women
with PCOS (the PregMet study [20]), metformin had no
impact on breastfeeding [21].
Recently, a small-scale phase I/II RCT of metformin
versus placebo has been conducted, with results pending,
to test whether metformin is safe and potentially eective
in treatinglow milk supplyin insulin resistant and pre-
diabetic mothers [28]. Primary outcome measures will
include milk output (at baseline and weeks 2 and 4
post-intervention), and secondary outcome measures
will include safety, mammary gene expression (using
mammary epithelial cell mRNA and RNA-sequencing),
sensitivity and specicity of maternal fasting plasma
glucose (FPG) in predictinglow milk supply, and change
inmilk output among completers. e results of this
study will inform a future larger double-masked RCT of
adjuvant metformin treatment versus placebo for early
postpartum low milk supply in women with insulin
resistance based on the presence of at least one of the
followings: Elevated FPG (dened as >95g/dL), history
of PCOS or gestational diabetes, or current abdominal
obesity.us, results of this pilot study are eagerly awaited
and will have a major impact on treatment strategies for
women with gestational diabetes, pre-diabetes, or PCOS
that present with low milk supply.
4. Metabolic Disturbances, Obesity, and
Breastfeeding
Animal models have demonstrated that obesity is
associated with marked abnormalities in mammary
alveolar development [29]. Mammary adipose tissue

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may produce locally eective concentrations of estrogen
that could alter mammary gland development and
lactation [17].
Approximately one-half of women with PCOS are
obese[30], and women with pre-gravid obesity, irrespective
of the presence of PCOS are less likely to initiate and
sustain breastfeeding [31,32]. Maternal obesity is also
associated with delayed onset of lactogenesis [33] and
a lower prolactin response to suckling [34]. erefore,
women with PCOS may be at an increased risk for
insucient milk supply due to their underlying obesity.
In the rst case-control study of breastfeeding in women
with PCOS, Vanky et al. reported reduced breastfeeding
rates in the early postpartum period in women with
PCOS; however, the controls were not matched for body
mass index (BMI). In the follow-up study of an RCT
of metformin versus placebo in pregnant women with
PCOS (the PregMet study [20]), the signicance of breast
growth in pregnancy, indexed by a change in bra size, on
breastfeeding outcomes was assessed [21]. e duration
of both exclusive and partial breastfeeding correlated
positively with breast size increment and the increase
in breast size was unrelated to maternal BMI or change
in BMI. Indeed, increased BMI was related to a shorter
duration of partial breastfeeding. Furthermore, those
with no breast growth were more metabolically disturbed
(obese had higher blood pressure, serum triglycerides,
and fasting insulin levels). e authors suggested a new
way of interpreting past epidemiological studies that
have shown breast milk to protect ospring from obesity
and diabetes [14,35,36]. Namely, because mothers with
decreased breastfeeding rates were more obese and had
higher insulin levels, their ospring may be more prone to
develop obesity, independent of breast milk. Simply put,
women who are not able to breastfeed are metabolically
inferior compared with those who breastfeed easily [21].
Similarly, studies examining the long-term benets of
breastfeeding on maternal metabolic risk factors have
yielded mixed results, and very few studies provide direct
evidence for lactation’s lasting eects on the development
of cardiometabolic diseases [37]. Although lactating
compared with non-lactating women have better metabolic
parameters, including lower lipid levels [38], lower fasting
and postprandial blood glucose [39,40], and greater
insulin sensitivity [39], few studies have measured these
biochemical parameters longitudinally [37]. Moreover, as
previously mentioned, it is dicult to ascertain whether
non-lactating women are at the start “metabolically
inferior” compared to lactating women [21]. erefore,
while breastfeeding may prevent the development of the
metabolic syndrome, pre-existing metabolic dysregulation
may hinder attempts at breastfeeding [41]. Women with
PCOS are at an increased risk of developing the metabolic
syndrome [42], and these characteristics may make them
more susceptible to lactation difficulties. One study
examined the eect of lactation on insulin resistance,
glucose and insulin metabolism, and biological markers
of insulin resistance (SHBG and insulin-like growth
factor binding protein-1 [IGFBP]) in fully breastfeeding
women with PCOS and normal lactating women during
the postpartum period as well as aer weaning [43].
12 lactating women with PCOS and six normal lactating
women were matched for BMI, and during the study,
BMI remained unchanged was comparable between the
groups. Lactation had no signicant eect on peripheral
insulin resistance (measured by the insulin tolerance test)
in women with PCOS, but fasting insulin concentrations
were lower aer weaning in the lactating PCOS group
than in the same patients before pregnancy. erefore,
although lactation may improve metabolic control in these
patients shortly aer weaning, the long-term benets
remain uncertain and should be investigated in future
prospective studies.
5. Conclusion
Studies, albeit scare, have reported conicting results
when examining breastfeeding success in women with
PCOS [11,12], and the divergence of the PCOS phenotype
may be responsible for the heterogeneous results to
date. Specically, insulin resistance as a feature of PCOS
may have a contributing or even essential role in the
development of lactation dysfunction and may be the
missing link. Considering the high prevalence of PCOS
among women of childbearing age and the known
benets of breastfeeding for both mother and child, it is
evident that more research in this area is needed. Future
research should focus on the underlying mechanisms

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54 Endocr Oncol Metab 2017; Volume 3, Issue 2 55Endocr Oncol Metab 2017; Volume 3, Issue 2
of PCOS-related low milk supply and further examine
the role of insulin resistance. is knowledge will help
design and implement interventions that will enable more
women with PCOS to meet their infant feeding goals.
Furthermore, understanding how insulin resistance and
PCOS aect lactation will broaden our understanding of
diabetes as a whole, potentially leading to new therapeutic
strategies for treating Type 2 diabetes.
References
1. World Health Organization. WHO. World Health Organization.
Available from: http://www.who.int/child-adolescenthealth/
nutrition/infantexclusive.htm. [Last cited on 2017Jun15].
2. Gartner LM, Morton J, Lawrence RA, Naylor AJ, O’Hare D,
Schanler RJ, et al. Breastfeeding and the use of human milk.
Pediatrics 2005;115:496-506.
https://doi.org/10.1542/peds.2004-2491.
3. Infant and Young Child Feeding-UNICEF DATA. Available from:
https://www.data.unicef.org/topic/nutrition/infant-and-young-
child-feeding. [Last cited on 2017Jun15].
4. Li R, Fein SB, Chen J, Grummer-Strawn LM. Why mothers stop
breastfeeding: Mothers’ self-reported reasons for stopping during
the rst year. Pediatrics 2008;122Suppl2:S69-76.
https://doi.org/10.1542/peds.2008-1315i.
5. Wagner EA, Chantry CJ, Dewey KG, Nommsen-Rivers LA.
Breastfeeding concerns at 3 and 7days postpartum and feeding
status at 2months. Pediatrics 2013;132:e865-75.
https://doi.org/10.1542/peds.2013-0724.
6. Ehrmann DA. Polycystic ovary syndrome. NEngl J Med
2005;352:1223-36.
https://doi.org/10.1056/NEJMra041536.
7. Krishnan A, Muthusami S. Hormonal alterations in PCOS and its
inuence on bone metabolism. JEndocrinol 2017;232:R99-R113.
https://doi.org/10.1530/JOE-16-0405.
8. Marasco L, Marmet C, Shell E. Polycystic ovary syndrome: A
connection to insucient milk supply? J Hum L act 2000;16:143-8.
https://doi.org/10.1177/089033440001600211.
9. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ,
DaviesMJ. e prevalence of polycystic ovary syndrome in a
community sample assessed under contrasting diagnostic criteria.
Hum Reprod 2010;25:544-51.
https://doi.org/10.1093/humrep/dep399.
10. Ip S, Chung M, Raman G, Chew P, Magula N, DeVine D,
et al. Breastfeeding and maternal and infant health outcomes
in developed countries. Evid Rep Technol Assess (Full Rep)
2007;153:1-186.
11. Vanky E, Isaksen H, Moen MH, Carlsen SM. Breastfeeding
in polycystic ovary syndrome. Acta Obstet Gynecol Scand
2008;87:531-5.
https://doi.org/10.1080/00016340802007676.
12. atcher SS, Jackson EM. Pregnancy outcome in infertile patients
with polycystic ovary syndrome who were treated with metformin.
Fertil Steril 2006;85:1002-9.
https://doi.org/10.1016/j.fertnstert.2005.09.047.
13. Riddle SW, Nommsen-Rivers LA. Acase control study of
diabetes during pregnancy and low milk supply. Breastfeed Med
2016;11:80-5.
https://doi.org/10.1089/bfm.2015.0120.
14. von Kries R, Koletzko B, Sauerwald T, von Mutius E, Barnert D,
Grunert V, et al. Breast feeding and obesity: Cross sectional study.
BMJ 1999;319:147-50.
https://doi.org/10.1136/bmj.319.7203.147.
15. Hilson JA, Rasmussen KM, Kjolhede CL. Maternal obesity and
breast-feeding success in a rural population of white women. Am
J Clin Nutr 1997;66:1371-8.
16. Tsilchorozidou T, O verton C, Conway GS. e pathophysiology of
polycystic ovary syndrome. Clin Endocrinol (Oxf) 2004;60:1-17.
https://doi.org/10.1046/j.1365-2265.2003.01842.x.
17. Neville MC, Anderson SM, McManaman JL, Badger TM, Bunik M,
Contractor N, et al. Lactation and neonatal nutrition: Dening and
rening the critical questions. JMammary Gland Biol Neoplasia
2012;17:167-88.
https://doi.org/10.1007/s10911-012-9261-5.
18. Kochenour NK. Lactation suppression. Clin Obstet Gynecol
1980;23:1045-59.
https://doi.org/10.1097/00003081-198012000-00008.
19. Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Pérez-Bravo F,
Recabarren SE. Maternal serum androgens in pregnant women
with polycystic ovarian syndrome: Possible implications in prenatal
androgenization. Hum Reprod 2002;17:2573-9.
https://doi.org/10.1093/humrep/17.10.2573.
20. Vanky E, Stridsklev S, Heimstad R, Romundstad P, Skogøy K,
Kleggetveit O, et al. Metformin versus placebo from rst trimester
to delivery in polycystic ovary syndrome: A randomized, controlled
multicenter study. J Clin Endocrinol Metab 2010;95:E448-55.
https://doi.org/10.1210/jc.2010-0853.
21. Vanky E, Nordskar JJ, Leithe H, Hjorth-Hansen AK, MartinussenM,
Carlsen SM. Breast size increment during pregnancy and
breastfeeding in mothers with polycystic ovary syndrome: A
follow-up study of a randomised controlled trial on metformin
versus placebo. BJOG 2012;119:1403-9.
https://doi.org/10.1111/j.1471-0528.2012.03449.x.
22. Schuring AN, Schulte N, Sonntag B, Kiesel L. Androgens and
insulin-two key players in polycystic ovary syndrome. Recent
concepts in the pathophysiology and genetics of polycystic ovary
syndrome. Gynakol Geburtshilfliche Rundsch 2008;48:9-15.
https://doi.org/10.1159/000111465.
23. Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N,
Medina F. Insulin stimulates testosterone biosynthesis by human
thecal cells from women with polycystic ovary syndrome by
activating its own receptor and using inositolglycan mediators
as the signal transduction system. JClin Endocrinol Metab
1998;83:2001-5.
https://doi.org/10.1210/jc.83.6.2001;
https://doi.org/10.1210/jcem.83.6.4886.
24. Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR,
Rittmaster RS, et al. Adirect eect of hyperinsulinemia on serum
sex hormone-binding globulin levels in obese women with the
polycystic ovary syndrome. JClin Endocrinol Metab 1991;72:83-9.

Kirigin Biloš et al.
54 Endocr Oncol Metab 2017; Volume 3, Issue 2 55Endocr Oncol Metab 2017; Volume 3, Issue 2
https://doi.org/10.1210/jcem-72-1-83.
25. Hummel S, Hummel M, Knopff A, Bonifacio E, Ziegler AG.
Breastfeeding in women with gestational diabetes. Dtsch Med
Wochenschr 2008;133:180-4.
https://doi.org/10.1055/s-2008-1017493.
26. Matias SL, Dewey KG, Quesenberry CP Jr, Gunderson EP. Maternal
prepregnancy obesity and insulin treatment during pregnancy are
independently associated with delayed lactogenesis in women with
recent gestational diabetes mellitus. Am J Clin Nutr 2014;99:115-21.
https://doi.org/10.3945/ajcn.113.073049.
27. Lemay DG, Ballard OA, Hughes MA, Morrow AL, HorsemanND,
Nommsen-Rivers LA. RNA sequencing of the human milk fat layer
transcriptome reveals distinct gene expression proles at three
stages of lactation. PLoS One 2013;8:e67531.
28. Available from: https://www.clinicaltrials.gov/ct2/show/results/
NCT02179788. [Last accessed on 2017 Apr 20].
29. Flint DJ, Travers MT, Barber MC, Binart N, Kelly PA. Diet-
induced obesity impairs mammary development and lactogenesis
in murine mammary gland. Am J Physiol Endocrinol Metab
2005;288:E1179-87.
https://doi.org/10.1152/ajpendo.00433.2004.
30. Roseneld RL, Ehrmann DA. the pathogenesis of polycystic ovary
syndrome (PCOS): e hypothesis of PCOS as functional ovarian
hyperandrogenism revisited. Endocr Rev 2016;37:467-520.
https://doi.org/10.1210/er.2015-1104.
31. Amir LH, Donath S. Asystematic review of maternal obesity and
breastfeeding intention, initiation and duration. BMC Pregnancy
Childbirth 2007;7:9.
32. Baker JL, Michaelsen KF, Sørensen TI, Rasmussen KM. High
prepregnant body mass index is associated with early termination
of full and any breastfeeding in Danish women. Am J Clin Nutr
2007;86:404-11.
33. Nommsen-Rivers LA, Chantry CJ, Peerson JM, Cohen RJ,
DeweyKG. Delayed onset of lactogenesis among rst-time mothers
is related to maternal obesity and factors associated with ineective
breastfeeding. Am J Clin Nutr 2010;92:574-84.
https://doi.org/10.3945/ajcn.2010.29192.
34. Rasmussen KM, Kjolhede CL. Prepregnant overweight and obesity
diminish the prolactin response to suckling in the rst week
postpartum. Pediatrics 2004;113:e465-71.
https://doi.org/10.1542/peds.113.5.e465.
35. Dewey KG, Heinig MJ, Nommsen LA, Peerson JM, Lönnerdal B.
Breast-fed infants are leaner than formula-fed infants at 1 y of age:
e DARLING study. Am J Clin Nutr 1993;57:140-5.
36. Mayer-Davis EJ, Rifas-Shiman SL, Zhou L, Hu FB, Colditz GA, Gillman
MW. Breast-feeding and risk for childhood obesity: Does maternal
diabetes or obesity status matter? Diabetes Care 2006;29:2231-7.
https://doi.org/10.2337/dc06-0974.
37. Gunderson EP. Impact of breastfeeding on maternal metabolism:
Implications for women with gestational diabetes. Curr Diab Rep
2014;14:460.
https://doi.org/10.1007/s11892-013-0460-2.
38. Knopp RH, Walden CE, Wahl PW, Bergelin R, Chapman M,
IrvineS, et al. Eect of postpartum lactation on lipoprotein lipids
and apoproteins. JClin Endocrinol Metab 1985;60:542-7.
https://doi.org/10.1210/jcem-60-3-542.
39. Tigas S, Sunehag A, Haymond MW. Metabolic adaptation to feeding
and fasting during lactation in humans. JClin Endocrinol Metab
2002;87:302-7.
https://doi.org/10.1210/jcem.87.1.8178.
40. Lenz S, Kühl C, Hornnes PJ, Hagen C. Inuence of lactation on oral
glucose tolerance in the puerperium. Acta Endocrinol (Copenh)
1981;98:428-31.
https://doi.org/10.1530/acta.0.0980428.
41. Stuebe AM. Does breastfeeding prevent the metabolic syndrome,
or does the metabolic syndrome prevent breastfeeding? Semin
Perinatol 2015;39:290-5.
https://doi.org/10.1053/j.semperi.2015.05.008.
42. Maliqueo M, Sir-Petermann T, Salazar G, Pérez-Bravo F, R ecabarren
SE, Wildt L. Resumption of ovarian function during lactational
amenorrhoea in breastfeeding women with polycystic ovarian
syndrome: Metabolic aspects. Hum Reprod 2001;16:1598-602.
https://doi.org/10.1093/humrep/16.8.1598.
43. Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS,
GhazziMN; PCOS/Troglitazone Study Group. Prevalence and
predictors of the metabolic syndrome in women with polycystic
ovary syndrome. JClin Endocrinol Metab 2006;91:48-53.
https://doi.org/10.1210/jc.2005-1329.