Hormones of Lactation: Too Much, Too Little? 1

Hormones of Lactation: Too Much, Too Little?
Estrogen ↑ →
Prolac n ↑
Human Placental
Lactogen * ↑
Progesterone ↑
More insulin resistant -
*Most closely related to breast volume
changes; Competes with prolactin for
receptors
© 2015 Lisa Marasco MA, IBCLC, FILCA
Normal
Milieu
[email protected]
Prolactin
Not enough
Oxytocin
Thyroid
PCOS
Obesity &
Estrogen
Androgens
Just right
HORMONE
TESTING
Estrogen ↓
Too much
Prolac n →
Human Placental
Lactogen ↓
Prolactin
Insulin
Thyroxine
Mammogenesis & Lactation
require a proper balance of
hormones for optimal development
Cortisol
Oxytocin
Estrogen↑
Er
Prolactin
PRLr
Progesterone
Thyroid
Oxytocin
Androgens↑
Insulin ↑
Progesterone ↓
Estrogen
More insulin sensitive +
Androgens
Pr
Muscle mass
& strength
Or
Ar
Bone
mineral
density
Ir
Energy
© Lisa Marasco 2015
Snyder, P. J. (2001). Editorial: The Role of Androgens in Women. J
1
Hormones of Lactation: Too Much, Too Little?
Free Androgen Index
(FAI):
Precocious pubarche…
too many androgens
too soon
S
A
Total T x 100
SHBG
Normal is 1%
-- 2% problematic
Most Androgens bind to SHBG or albumin
Estrogen stimulates
development of
mammary tissue
E↑
SHBG ↑ with estrogen, thyroid hormone,
pregnancy
T↓
Androgens slow growth
of mammary tissue
(possibly by ↓ERα)
When SHBG ↓ more Androgens are free to
circulate
SHBG ↓ w/ Androgens, Synthetic progestins,
glucocorticoids, GH, Insulin, Obesity,
Hypothyroidism, Hyperinsulinemia
Labrie F. Dehydroepiandrosterone, androgens and the mammary gland. Gynecology Endocrinology 2006; 22(3):118-30.
Liver:
Sex Hormone
Binding Globulin
Adrenals:
Dehydroepiandrosterone sulphate
[DHEA-S] (90-100%)
Dehyroepiandrosterone [DHEA] (80%)
Androstenedione (50%)
Testosterone (25%)most active form of androgen
Ovaries:
DHEA (20%)
Androstenedione (50%)
Testosterone (50%)
Testosterone
precursors
Peripheral Tissues:
convert DHEA into
more Testosterone &
Dihydrotestosterone
for local use- not
measurable in blood!
 Pre-eclampsia (Serin, 2001)
 Infant growth restriction (Carlsen, 2006)
 Increased mastopathies (Volobuev, 1990)
 More pregnancy complications (Palomba, 2009)
 Decreased prolactin (Aisaka 1984)
 Decreased lactation (Carlsen 2010, Aisaka 1984)
 Delayed lactation (Hoover, 2002; Betzold, 2004)
Somboonporn W, Davis S. Testosterone Effects on the Breast: Implications for testosterone therapy for women
© Lisa Marasco 2015
2
Hormones of Lactation: Too Much, Too Little?
Carlsen2010
Polycystic
Ovary
Syndrome
Negative breastfeeding association
Testosterone
Experimental:
Women at risk of
SGA infant



DHEA

3 wks & 6 mos
Blood drawn @
25wks gestation
3 & 6 mos
Controls:
Random selection
Androstenedione Free T Index
“Mid-pregnancy androgen levels are negatively associated with
breastfeeding”
Diagnostic Criteria
Rotterdam 2003 Consensus: 2 of 3
Not enough
Delayed pubarche
Low sex drive
Just right
Too Much
Good breast
↓ Breast develop/growth?
development,
↓ Prolactin receptors &
milk production ↓ Milk Production
 Clinical/biochemical hyperandrogenism
 Oligo/anovulation
 polycystic ovaries
Androgen Excess Society 2006: both
 Clinical/biochemical hyperandrogenism
 Ovarian dysfunction (oligo/anovulation and/or PCO)
National Inst of Health (NIH) 1992: both
 Clinical/biochemical hyperandrogenism
 Menstrual dysfunction
*All require exclusion of other causes of androgen excess
Dual Population for PCOS
 Laboratory history of hyperA?
 Hx of pre-eclampsia or SGA infant?
 Physical symptoms of hyperA?
 Hirsutism- ask!
 Adult acne
 Androgynous build
 Onset of above symptoms?
 50-70% obese; 30-50% with normal BMI
 Other hormonal imbalances
- Too much estrogen (estrogen dominance)
- Too little progesterone
- Concomitant hypothyroidism
Hormonal profiles differ for thin versus
obese women
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
metformin
Endocrine issues & Clinical problems
↑ Androgens, ↓ SHBG → hirsu sm, acne, alopecia
↓ Insulin Resistance
↑
→ Hyperinsulinemia
↓
Higher expression
Reduced
expression
of PTPRF
Insulin resistance → hyperinsulinemia, acanthosis
nigricans, skin tags, central obesity, diabetes
↓ Ovarian androgen
↑
production (Testosterone,
Androstenedione, DHEA)
Less serum
High
serum
androgens
Up-regulate
Estrogen
& &
Down-regulate
Estrogen
Prolactin Receptors
Reduced Lactation Capacity
Improved Lactation Capacity
& Milk Production!
Thanks to R. Craig, MD
Tell-tale signs of hyperandrogenism
During the next pregnancy
Facial hair,
acne
 Metformin reduces miscarriages,
gestational diabetes, preeclampsia, premature births
 Treatment during pregnancy may
help with breast growth (anecdotal)
 Pregnancy treatment may also
reduce a baby’s girl’s exposure to
too many androgens
Glueck, 2002, 2004, Carlsen, 2010
Insulin resistance
Interference
w/removal of
insulin by liver
Retrospective 1 yr postpartum, 186 participants
Looked at pre- to late- pregnancy bra sizes, Androgens
Increased insulin
Results:
• No difference in breast increments between met and control
• Breast size change postively correlated w/ duration of bfg; BMI neg
More free
androgens
• No correlations between DHEAS, T, FTI & br increment or duration
• Women w/ no changes more obese, high BP, shorter duration
↓ SHBG produc on in liver;
↑ Ovarian androgens
Schuring et al. Androgens and Insulin- Two Key Players in Polycystic Ovary Syndrome. Gyn Geb Rundsch 2008; 48:9-15.
Carlsen, S. M., & Vanky, E. (2010). Metformin influence on hormone levels at birth, in PCOS mothers and their newborns. Hum Reprod, 25(3), 786-90.
Vanky, et al (2012). 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.
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
Conclusion:
“Metformin and androgens had no
impact on breastfeeding. Women
with PCOS who had no breast size
increment in pregnancy seemed to
be more metabolically disturbed
and less able to breastfeed”
BUT
dexamethasone
↓ Insulin Resistance
↓ Adrenal androgens
↓ Hyperinsulinemia
metformin
Even Less
Less serum
serum
androgens
androgens
↓ Ovarian androgen
production (Testosterone,
Androstenedione, DHEA)
Further
Up-regulate
up-regulation
Estrogen
of&
Estrogen
Prolactin
& Prolactin
ReceptorsReceptors
Improved
Optimized
Lactation
Lactation
Capacity
Capacity
Vanky, et al (2012). 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.
Thanks to R. Craig, MD
Then what about this one?
1st baby 2000, no br changes
Asymmetrical breasts
Milk “didn’t seem to come in”
Same 2001, 2003. Max .25oz
Decided to con’t metformin
1500mg throughout 4th
pregnancy- exp br changes
• Added domperidone @1wk, made
½ baby’s needs this time
•
•
•
•
•
“I call Metformin my wonder drug. It gave me a gift
that I would have swapped almost anything for.”
PCOS
Insulin
Resistance/
Diabetes
↓ Prolactin
Response
Hypertension
Hypoplasia
Rasmussen, K. (2007). Association of maternal obesity before conception with poor
lactation performance.
Nommsen-Rivers, L. A., Chantry, C. J., Peerson, J. M., Cohen, R. J., & Dewey, K. G. (2010).
Delayed onset of lactogenesis among first-time mothers is related to maternal obesity and
factors associated with ineffective breastfeeding..
Hilson, J. A., Rasmussen, K. M., & Kjolhede, C. L. (2006). Excessive weight gain during
pregnancy is associated with earlier termination of breast-feeding among White women.
Rasmussen, K. M., Hilson, J. A., & Kjolhede, C. L. (2002). Obesity as a risk factor for failure
to initiate and sustain lactation.
Chapman, D. J., & Perez-Escamilla, R. (1999). Identification of risk factors for delayed
onset of lactation.
Low dose dexamethasone (.25mg/day)
Reduced androgens further in women
with PCOS already taking metformin and
making diet & lifestyle changes
Compared to placebo:
Testosterone ↓ 27%
Androstenedione ↓ 21%
DHEAS ↓ 46%
Free T index ↓ 50%
High BMI + excessive wt gain =
additive risk
Hilson, 2006
IOM
Overweight
15-25 lbs
BMI 26-29
Obese
BMI > 29
Vanky, 2004. Six-month treatment with low-dose dexamethasone further reduces androgen levels in
PCOS women treated with diet and lifestyle advice, metformin.
© Lisa Marasco 2015
13-20 lbs
<IOM OR Within OR >IOM OR
2.96
1.47
1.62
1.81
1.84
2.89
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Hormones of Lactation: Too Much, Too Little?
High BMI
Normal BMI
Breast development
Blunted PRL response, HyperA
problems
risk, Highpuberty/pregnancy
estrogen, IR risk,
Lower milk production risk
Pregnancy:
Increased demand
for thyroid hormone
Low BMI
Stimulates ductile
Normal metabolism,
development,
hormonesprolactin
for lactation
Medications
Environmental contaminants
ie. Perchlorate, Cadmium
Cigarettes: cause Higher
free T3, T4; Increased risk for
Graves, hyperthyroidism
DIET: Lack of iodine foods
Hypothyroidism
High TSH verified by low T3/T4
 Influences breast tissue
via prolactin & GH
Sx may include weight gain, cold, fatigue,
hair loss
T3 = triiodothyronine
T4 = thyroxine
New suggested TSH range for
fertility/early pregnancy .5-2.5 → may
flag more of those “borderline” cases
TSH = Thyroid-stimulating
hormone Indicator of
thyroid function
www.mirage-samoyeds.com
http://commons.wikimedia.org/wiki/File:Thyroid_system.svg
Pregnancy impact
Can be primary, secondary,
overt, subclinical, autoimmune
Can also occur
in conjunction
with other
conditions
such as PCOS
Onset can be
prior to preg,
during preg,
post-delivery,
or even later
DubaiChronicle.com. Used with permission
Incidence much higher in women
Thyroid hormone requirement
↑ 30-40%
Pregnancy loss rate in first trimester beyond wk 10
TSH < 2.5 mIU/I = 3.6%
TSH 2.5-5.0 mIU/I = 6.1%
Positive antibodies 2-fold risk of miscarriage
Negro, R., Schwartz, A., R, G., Tinelli, A., Mangier, i. T., & Stagnaro-Green, A. (2010). Increased Pregnancy Loss Rate in Thyroid Antibody Negative Women
With TSH Levels Between 2.5 and 5.0 in the First Trimester of Pregnancy. J Clin Endocrinol Metab, 95, E44-48.
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
Hypothyroid
Hypothyroidism in Pregnancy
Uncontrolled hypothyroidism can cause
→ anemia
→ pregnancy induced hypertension
→ postpartum hemorrhage
Risk factors
for delayed
Lact 2
Reproductive Endocrinologist
perspective
Proposed new TSH range for fertility/early
pregnancy is .5-2.5, with 1.0 as ideal
→ may flag more of those “borderline” cases
Controversial- not yet settled
Hypothyroid rats have
smaller litters and
longer gestations
Decreased GH, IGF-1,
circulating Triglycerides,
& milk-making tissue
during pregnancy as
well as a reduction in
circulating oxytocin
postpartum with
impaired milk ejection
& lactation (Hapon 2003, 2005)
Low TSH verified by elevated
T3/T4
 Grave’s disease most common
 Common sx include weight
loss, fast heart beat, sleep
problems, nervousness,
frequent BMs
 Previously thought not to
affect lactation
http://www.mja.com.au/public/issues/180_04_160204/top10414_fm.html
Normal
Hypothyroid
Sx often improve during
pregnancy, but more
severe HT can cause
pregnancy complications
such as fetal growth
restriction, pre-eclampsia,
preterm labor.
Fig. 3. The effects of thyroid hormones and progesterone (P) on tertiary branching. Whole mounts of
mammary glands from mice are presented. (A) 3-month-oldC3Hmouse; (B) 3-month-old hypothyroid
C3H mouse, after treatment with propylthiouracil for 5 weeks; (C) 3-month-old hyperthyroid C3H
mouse, treated with thyroxine for 5 weeks; (D) 39-day-old BALB/c mouse (reproduced by permission
of the Society for Endocrinology; 58); (E) 39-day-old intact BALB/c mouse treated with P for 15 days
(reproduced by permission of the Society for Endocrinology; 58).
Hovey, R. C., Trott, J. F., & Vonderhaar, B. K. (2002). Establishing a framework for the functional mammary
gland: from endocrinology to morphology. J Mammary Gland Biol Neoplasia, 7(1), 17-38.
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
Normal
Hypothyroid
Hyperthyroid
Shana… another hyperT case
Weight loss, hair loss,
heart palpitations,
anxiety, mood swings,
period stopped
Aug Labs: TSH- 0.01,
Thyroid antibody+
Sx fade, labs
improve, period
Became pregnant.
returns, but cycle is No complications
every 40-45 days.
Anovulatory
May-Aug 2005 Oct 2005
Fig. 3. The effects of thyroid hormones and progesterone (P) on tertiary branching. Whole mounts of
mammary glands from mice are presented. (A) 3-month-oldC3Hmouse; (B) 3-month-old hypothyroid
C3H mouse, after treatment with propylthiouracil for 5 weeks; (C) 3-month-old hyperthyroid C3H
mouse, treated with thyroxine for 5 weeks; (D) 39-day-old BALB/c mouse (reproduced by permission
of the Society for Endocrinology; 58); (E) 39-day-old intact BALB/c mouse treated with P for 15 days
(reproduced by permission of the Society for Endocrinology; 58).
June 2006 Sept 2006
Dx’d Thyroiditis. Treated
with steroid for 1 mo
Hovey, R. C., Trott, J. F., & Vonderhaar, B. K. (2002). Establishing a framework for the functional mammary
gland: from endocrinology to morphology. J Mammary Gland Biol Neoplasia, 7(1), 17-38.
Rat studies showed good mammary growth
and evidence of milk production but poor or
complete lactation failure depending on the
degree of hyperT
April 2007
Thyroid checked during
third trimester.
Apr results normal:
TSH- 1.43, T4- 0.9
Shana…
Extreme wt loss, hair Some relief of sx.
Gave birth to son.
Normal but very long loss, fatigue, dizzy
Milk supply coming
spells, insomnia.
labor and delivery.
down.
June 2007 mid-July 2007 Sept 2007 Oct 10 2007 Nov 2007
Problem was pinpointed to oxytocin release
and milk ejection (Varas 2002)
Dx’d hyperthyroid in
18th week, TSH .0006
Developing nursing
difficulties. Overactive
MER, oversupply
Thyroid antibody positive
Thyroid very high,
TSH- 0.019, T3- 8.4.
Prescribed PTU.
 Breasts grew 36C→36DD++
 Delivered 36wks, med ↓
to 50mg day before
 Could not pump anything
out, could hand express
little
 EXTREME ENGORGEMENT
 No MER
Personal or fam hx of thyroid dysfunction?
Significant changes in energy, fatigue?
Sluggish or rapid preg breast changes?
Hx of infertility, meds like cabergoline
or bromocriptine
Personal or family hx of autoimmune
problems? Alcoholism?
 Stopped bfg after 1 wk
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
Thyroid hormone replacement
is first line of treatment for
hypothyroidism-related supply
problems… The Armour debate
Reducing thyroxine is the first
line of defense for
hyperthyroidism- related milk
supply problems
Hypo T (Low)
Just right
Poor milk production
Sluggish MER/OT
Good milk
production
HyperT (High)
Onset pre-conception,
antenatal or postpartum?
Hyper-production
Inhibited OT/MER
Beware of over- or undertreatment postpartum
Hypothalamus
(Hypophysis)
Oxytocin
nasal spray?
Anterior pituitary
(Adenohypophysis)
Posterior pituitary
(Neurohypophysis)
If MER a problem, may possibly provide the
oxytocin needed for milk ejection exogenously
while waiting for hormone correction to boost
natural oxytocin
Ashwagandha- stimulates T3
Chickweed- supportive
Dandelion- supportive
Milk thistle- improves T4→T3
Nettle- supportive/balancing
Vervain- supportive
Red clover- increased total & free T3 in ewes
Fenugreek- Reduced T3 in mice & rats
Lemonbalm (Melissa officinalis)- considered anti-hyperT
Malunggay- tested for use with hyperthyroidism
Yarnell 2006; Tahiliani 2003; Panda 1999;
Normally about the size of a
But doubles in size during pregnancy due
to (↑E→) hyperplasia and hypertrophy of
prolactin-secreting cells (lactotrophs)
Pituitary
lactotrophs
synthesize
prolactin
#1 target is the breast,
for lactation
Stimulation of mammary
tissue
Critical for milk-making cell
survival, tight junctions
Stimulation of milk
synthesis, lipids
Also has immune functions
© Lisa Marasco 2015
Mammary epithelial
cells (MEC) /lactocytes
Suckling &
touch stimuli
9
Hormones of Lactation: Too Much, Too Little?
Source: http://www.vce.bioninja.com.au/aos-2-detecting-and-respond/coordination--regulation/endocrine-system.html
Target cell same
as signaling cell
Prolactin
Target cell distant
from signaling cell
Target cell near
signaling cell
Pituitary
Prolactin
Prolactin
Extra-Pituitary
Lactocyte
Lactocyte
Lactocyte
© 2013 Miguel Ángel Castaño López, José Luís Robles
Rodríguez and Marta Robles García. Originally published in
Intech under CC BY 3.0 license. Available from:
http://dx.doi.org/10.5772/54758 The data was taken from
Benavides IZ, Castillo AP, Montemayor I, DeEstrada
R,Onatra W, Posso H. Biorritmo de prolactina en mujeres de
edad reproductiva vs.Perimenopáusicas.Rev Coloma
Menop.2003;9:153–8.[16 Sep 2009].
In mouse studies, MEC autocrine prolactin is required for differentiation
in late pregnancy as well as initiation of lactation- Chen 2012
Genetic Science Learning Center, University of Utah, http://learn.genetics.utah.edu.
Monomeric
or “little”
prolactin
Aggregate or
“big-big” or
macroprolactin
Dimer or
“big”
prolactin
© 2013 Miguel Ángel Castaño López, José Luís Robles Rodríguez and Marta Robles García. Originally published in Intech
under CC BY 3.0 license. Available from: http://dx.doi.org/10.5772/54758 The data was taken from Fuchs, F. y Koppler A.
Endocrinología de la Gestación. 1982. Segunda edición. Salvat Editores,S.A. Capítulo 12. Pag. 249-72
*Conversion factor: mU/l × 0,0472 =ng/ml; ng/ml × 21,2 = mU/l.
Wikipedia: http://www.ebi.ac.uk
PRLr-Long
PRL
Most abundant, primary for lactation.
Activates Stat 1, 3, *5a, *5b
PRLr-Int
Promotes cell survival
PRLrS1a
???
PRLrS1b
Strongly interferes with LONG signaling;
growth/proliferation limiter?
Receptor affinity changes
Receptors up- and down-regulate
Expression of types (Long, Inter, Short 1a & 1b) change
Prolactin can be displaced from its
receptor
http://scrippslabs.com/scripps-news-volume-16-number-1/
Alveolar distention distorts receptors, prevents uptake
O'Leary, P., Boyne, P., Flett, P., Beilby, J., & James, I. (1991). Longitudinal assessment of changes in reproductive hormones during normal pregnancy.
Clin Chem, 37(5), 667-672.
“There is clearly a need to examine those changes that occur during normal
pregnancy so that unusual or unexpected trends can be identified…
© Lisa Marasco 2015
10
Hormones of Lactation: Too Much, Too Little?
© 2013 Miguel Ángel Castaño López,
José Luís Robles Rodríguez and Marta
Robles García. Originally published in
Intech under CC BY 3.0 license.
Available from:
http://dx.doi.org/10.5772/54758 The
data was taken from Tyson JE, Hwang
P, Guyda H, Friesen Hg. Studies of
prolactin secretion in human
pregnancy. Am J Obstet Gynecol
1972;113:14-20.
“…a relatively low basal level and
“Good lactators
gave a
a moderate
feeding-induced
prolactin
response
236% of
response
are
early indicators
above and
baseline
[doubled]
delayed
less productive
lactation…
In unfavourable
cases,
after nursing
whereas poor
the
feeding-induced
increases
lactators
showed aPRL
blunted
gradually
disappeared
and1990
Ostrom,
or flat response”lactation stopped”- Godo 1988
Interesting note: Higher progesterone & prolactin
during pregnancy associated with greater milk
output at 1 wk- Ingram 1999
Driven by estrogen
during pregnancy
Influenced by frequency
& quality of stimulation
PRL clearance = 180 min;
>8x sustains elevation (Cox 1996)
200-400 ng/mL
60-110ng/mL
8-20 ng/mL
Preg 0
3mo
Multips had lower levels,
likely due to more receptors
& binding (Ingram 1999)
Baseline a product of surges
Trott 2012
Pregnancy
6mo
BIRTH
Non-lactating
1 mo
2 mo
Primips had higher
serum prolactin levels
3mo 4mo 5mo 6 mo
9mo
“…effect of prolactin may be more related to the density of
the prolactin receptor abundance or affinity or both than to
the circulating PRL concentrations…”
Nedkova 1995 (Bulgarian)
Studied effect of early initiation on PRL in 90 women:
All newly delivered mothers had serum PRL level over
100ng/ml, author accepted as minimum threshold
Initiation of breastfeeding
< 6 hrs post-delivery
@ 6-12 hrs post- delivery
@ 72 hrs post-delivery (c-sections)
*Feeding frequency unknown, likely q4hrs
Prolactin on Day 4*
164
124
29
8am 9 10 11 12 1pm 2 3 4 5 6
7
8
9 10 11 12am 1 2 3 4 5 6 7
Stern, J. M., & Reichlin, S. (1990). Prolactin Circadian Rhythm Persists throughout Lactation in Women.
Neuroendocrinology, 51(1), 31-37.
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
Uvnäs-Moberg 1990
o “Basal PRL levels recorded
at 3-4 mo postpartum closely
related to remaining period of breastfeeding”
o “Mixed feeding” mothers consistently had
lower prolactin levels than mothers who were
exclusively breastfeeding
HYPOPROLACTINEMIA
(PROLACTIN DEFICIENCY)
Figure 1. Prolactin concentrations in the blood
of gilts (young primip pig) receiving an empty
capsule (CTL) or 10 mg bromocriptine (Bromo)
thrice daily from d 70 to 110 of gestation
Figure 4. Transversal cut from the mammary gland of gilts receiving
an empty capsule (C, placebo) or 10mg of bromocriptine (B) thrive
daily from d 70 to 110* of gestation
Farmer, C., Sorensen, M. T., & Petitclerc, D. (2000). Inhibition of prolactin in the last trimester of gestation decreases mammary gland development in gilts. J
Anim Sci, 78(5), 1303-1309.
Family history of alcoholism
Diagnosed by low/undetectable levels of PRL
that fail to rise upon stimulation with TRH, etc.
Smaller prolactin response to
breast stimulation
Infants fed more often in late
afternoon
Clinical manifestation limited to failure of milk
production
Considered rare; 6 cases of isolated deficiency
in the literature
Prolactin resistance? Hypothetical Zargar 2000
Mennella, J. A., & Pepino, M. Y. (2010). Breastfeeding and prolactin levels in lactating women with a family history of alcoholism. [Randomized Controlled Trial Research
Support, N.I.H., Extramural]. Pediatrics, 125(5), e1162-1170. doi: 10.1542/peds.2009-3040
Potential causes:
Medications: bromocriptine, cabergoline,
pyridoxine, diuretics, nicotine
Vascular lesions, PP pituitary necrosis aka Sheehan's
Cranial Radiotherapy (CRT) tx at young age
Anterior pituitary impairment 2° to pituitary tumor,
infection
→ Anterior pituitary problems- GH, PRL
Prolactin declines further over time
Head injury
Infection (tuberculosis, histoplasmosis)
Infiltrative diseases / Autoinflammatory conditions, i.e.
sarcoidosis, hemochromastosis, lymphocytic hypophysitis
Theory: GH influences prolactin secretion directly
OR indirectly through IGF-1
High lactation failure rate
Follin: 6 of 7; Johnston: 10 of 12
Johnston, K., Vowels, M., Carroll, S., Neville, K., & Cohn, R. (2008). Failure to lactate: a possible late effect of cranial radiation. Pediatr Blood Cancer, 50(3), 721-722.
Follin, C., Link, K., Wiebe, T., Moell, C., Bjork, J., & Erfurth, E. M. (2013). Prolactin insufficiency but normal thyroid hormone levels after cranial radiotherapy in longterm survivors of childhood leukaemia. Clin Endocrinol (Oxf), 79(1), 71-78.
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
Case I: Treated w/bromocriptine prior to pregnancy; levels rose
normally then extra high (~600ng), headache @ 39 wks for 6 hrs.
Case 2: Treated with CRT (Cobalt Radiation Therapy); Twins
Case 3: Tumor removed surgically. Twin pregnancy.
Postpartum hemorrhage
Damage to pituitary: mild  Sheehans 
2
1
2
3 1
3
Batrinos, M. L., Panitsa-Faflia, C., Anapliotou, M., & Pitoulis, S. (1981). Prolactin and placental hormone levels during pregnancy in
prolactinomas. Int J Fertil, 26(2), 77-85.
None were able to breastfeed…
Image: Zak I T et al.
Radiographics 2007;27:95-108
Batrinos, M. L., Panitsa-Faflia, C., Anapliotou, M., & Pitoulis, S. (1981). Prolactin and placental hormone levels
during pregnancy in prolactinomas. Int J Fertil, 26(2), 77-85.
Shahzad, H., Sheikh, A., & Sheikh, L. (2012). Cabergoline therapy for Macroprolactinoma during pregnancy: A case report.
BMC Research Notes, 5(1), 606. Used with permission.
Often treated w/ PRL inhibitors, radiation or surgery
Hx of galactorrhea is no guarantee of good lactation
Sporadic information
Cheng, W., & Zhang, Z. (1996). [Management of pituitary
adenoma in pregnancy]. Zhonghua Fu Chan Ke Za Zhi, 31(9),
537-539. 75% breastfed
http://www.women-health-info.com/33-Hyperprolactinemia-Lactation.html
Iwama Case Study
• Previously diagnosed @ 33 with Hashimoto’s hypoT,
normalized w/treatment
• First pregnancy @ 36, no milk. PRL 6.5ng/mL on day 10,
undetectable 10d later even with dom.
• Second baby at 39, same outcome. undetectable PRL. Good
breast development.
• Genetic studies found no problems, BUT... Discovered
auto-antibodies that specifically targeted prolactinsecreting cells
√√ DeBellis 2013 also involved antibodies to GH and PRL
• Developed full supply for duration of recombinant hPRL
study
Iwama, S., Welt, C. K., Romero, C. J., Radovick, S., & Caturegli, P. (2013). Isolated prolactin deficiency associated with serum
autoantibodies against prolactin-secreting cells. J Clin Endocrinol Metab, 98(10), 3920-3925. doi: 10.1210/jc.2013-2411
Public domain. http://www.loc.gov/pictures/item/91721203/ Kurz and Allison; Adam Cuerden
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
“big-big” or
macroprolactin
Not enough
Normal: rising→200-400ng
Poor mammary cell
proliferation & differentiation
High
Natural hyperprolactinemia:
drives breast changes
Radavelli-Bagatini, et al. (2013). Macroprolactinemia in women with hyperprolactinemia: a 10-year follow-up. Neuro Endocrinol Lett, 34(3), 207-211.
Shimatsu, A., & Hattori, N. (2012). Macroprolactinemia: diagnostic, clinical, and pathogenic significance. Clin Dev Immunol, 2012, 167132.
http://www.infantrisk.com/content/presence-macroprolactinemia-mothers-insufficient-milk-syndrome
Not enough
Poor milk production
Loss of alveoli
-0-
No known
negative effects
Normal: 0-20ng
Just right
# varies by stage
good milk
production
HyperPRL:
treated or untreated?
Poor milk
production?
Did the milk ever come in?
Too much >20ng
Hx of pp hemorrhage, acute hypotension?
Hyperprolactinemia:
suppression of ovulation
Hx of pituitary problems or tumors?
Hx of infertility, meds like cabergoline
or bromocriptine
Personal or family hx of autoimmune
problems? Alcoholism?
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
Past history of
unexplained lactation
failure in presence of
good breast growth
Lack of normal-appearing
breast response to
pregnancy
“These findings… add further
weight to the importance of serial
prolactin measurements as a
reflection of the functional state of
the pituitary during gestation.”
– Batrinos, 1981
Laboratory Measuring issues:
Check 3rd trimesterminimum 150-250 ng/mL
(mcg/L). Consider E2 also.
“The author recommends that female patients
who are interested in lactation and have
suspected anterior pit dysfunction have Prolactin
measured in the third trimester of pregnancy, or
peripartum”- Benson 2008. (Also suggested TRH
Bound vs Unbound prolactin
Receptors
Labs have no reference ranges for lactation!
Must factor in frequency of feeding/pumping
when interpreting results
Primip/multip status effect?
challenge to confirm, as well as check LH FSH, TSH and FT4)
Failure of
lactation with
appropriate
appearing breast
tissue
Unexplainable decrease in
milk production despite
good management, no
other risk factors
PRL level
following
administration
of TRH or
domperidone?
“The work should also alert
physicians to the possibility of PRL
deficiency from causes other than
Sheehan’s syndrome in mothers
who fail to lactate”- Iwama 2013
“Considering the well-known relationship between
pregnancy & autoimmunity, an early post-delivery
immunological and functional investigation in women
presenting with disorders of lactation may be useful to
detect potential pituitary and thyroid dysfunction even
at a subclinical stage”- DeBellis 2013
Measuring prolactin
For Basal/Baseline level:
After 2-3 hours no stimulation
N/A
For Surge:
30-45 from start of
nursing/pumping
Replacement therapy
© Lisa Marasco 2015
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Hormones of Lactation: Too Much, Too Little?
Weight Gain
Androgens
Obesity
Insulin Resistance/
Diabetes
 What are your suspicions, and why?
 When to ask
 Who to ask
 How to ask
What to ask
Look at lab ranges
Is this a hormone that is affected by
pregnancy or lactation?
Develop your expert contact network
Bound versus unbound
hormone
Does not measure
peripheral tissue
hormones
May not account for
receptor issues
Subclinical conditions
may not show up with
standard tests
Look for obvious abnormalities
Please remember:
Explain to mother the possible
implications if significant
We Know Not because We Ask Not
Discuss mother’s options based on
what you know
Write summary of concerns to HCP
Is it really WNL?
Possible phone call to explain or
expedite action
Or did we just assume this?
© Lisa Marasco 2015
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