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Hormonally induced mammary hairs Э of a primitive rodent Aplodontia rufa.

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HORMONL4LLP INDUCED ‘ ‘ XAILINARY HAIRS ” O F A
PRIMITIVE RODENT APLODONTIA RUFA
E. W. PFEIFFER
Xiisrum of Vertebrate Zoology, Universaty of Calafornia, Berkeley
SEVEN FIGURES
Certain feniale B p l o d o ~ z f i ucaptured in the spring aiid surnmer have dense patches of black hairs (“mammary hairs”)
around the nipples (Taylor, ’18). Since juvenile females and
anestrous, parous females taken just prior t o the breeding
season showed no such patches, and since both pregnant and
lactating and non-pregnant females with corpora lutea showed
them, one or more of the female reproductive hormones
seemed t o be involved in the production of these hairs. During
an investigation of the reproduction of this primitive rodent,
an effort was made t o analyze this liormoiial control.
A similar phenomenon has been reported in the porcupine.
Struthers (’28) states that the hairs around the nipples of
pregnant female porcupines are diffexnt in color from those
of non-pregnant females. An apparently related phenomenon,
pigmentation of the epidermis of the nipples and surrounding
area during pregnancy, is common in many mammals including man (Turner, ’39), but according to Cathcart et al. (’48)
has never been given a satisfactory explanation. However,
Davis et al. (’45) give a detailed account of the clinical and
experimental evidence that physiological pigmentation in
man aiid guinea pig is related t o pituitary-gonadal function.
Increased amounts of estrogen during pregnancy predispose
the nipples, areolae, and linca nigra t o hyperpigmentation.
Estrogen was shown t o produce pigmentation in guinea pigs
of both sexes and in premenopausal, but not in postmenopausal women. Functional changes of the anterior lobe are
241
242
E. W. PFEIFFER
suggested a s interfering with pigmentation in the latter case.
L4ccording to these authors the direct effect of estrogen on
the melanoblasts was demonstrated by unilateral inunction
of estrogen which was followed by pigmentation on the estrogeriized side only. Cliorionic gonadotropin inhibited pignientation in guinea pigs, but not the hypertrophy, while equine
gonadotropin did not interfcre with the estrogen-induced
effect. Neither progesterone nor prolactin had any effect on
pigmentation, although the evidence is inconclusive since none
of the subjects were hypophysectomized.
Among some of the lower mammals the effects of estrogen
upon the integument and its appendages have been investigated. Williams et al. ('46) state that estrogens elicit some
reactions indirectly by first stimulating the pituitary which
in turn acts upon a n end organ. Hooker arid Pfeiffer ('43)
demonstrated that injection of estrogen into r a t s greatly retarded the regrowth of hair in shaved areas and also caused
thinning of the epidermis, atrophy and loss of sebaceous
glands, and atrophy of hair follicles. Ingle ('51) states,
however, that the action of injected estrogen is mediated
largely through the pituitary-adrenal axis. Wilkins ( '50)
and Hamilton ('51) indicate that androgens are responsible
for the production of secondary sexual hair in humans.
To my knowledge, there a r e no reports indicating the involvement of the female reproductive hormones in the growth
of hairs such as the mammary hairs of Aplodofitia. However,
Carlisle ( '54) describes results of experiments on the mamniae
of male rabbits that closely resemble, in certain respects, the
results described below. This author found that injections of
estrogen and progesterone into male rabbits induced the development of extra mammary lobes and suggests that they
a r e derived from hair follicles and sebaceous glands. This
treatment caused hypertrophy of sebaceous glands and of
the openings of the hair follicles. Enlargement of the latter
occurred only distally to tlie opening of the sebaceous gland
duct ; the hair root degenerated. Because the growth of mammary hairs in ApZodontift seenis to be related to incompletely
MAMMARY HAIRS O F APLODONTIA
243
understood changes i n the mammary epidermis of many mammals, a n investigation was undertaken to determine which of
the ovarian hormones might be involved. Prolactin was also
tested since the changes in mammary hairs in the wild population occurred when prolactin is thought to be at a high level
and because this hormone affects the epidermis of birds
(Bailey, '52).
MET EIODS
B p l o d o d i n were trapped alive and comparatively undarnaged in the Point IZcyes area of Rlarin County, California.
They were maintained in good health in small laboratory
cages and fed P u r i m Laboratory Chow and fresh fruits and
vegetables. The hormones m i - e injected or applied by inunction topically as indicated in table 1 both before and after
castration. Mammae of treated animals were removed surgically at various stages of development of the reaction and
were compared to the mammae of controls, t o inireactive areas
of their own abdomens, and to the manimae of intact feniales
trapped at various stages of the reproductive cycle. The
niammae were fixed in Bouin's, imbedded in paraffin, sectioned
a t 8 p, and stained with Galigher 's heniatoxylin and eosiii
(Galigher, '34). The skin over the mmirriae of certain specimens was removed and dried to study the degree of pigrncntation aiid hair growth occurring.
I n order t o determine quantitatively wliat changes were
occurring and whether or not the artificially induced cliaiiges
were comparable to those observed in thc mild animals, saiiiples of about 100 belly hairs and 100 manivnary hairs were
cut froni appropriate specimens and the widths of individual
hairs and the number of hairs of various widths per sample
W C ~ Ccompared. Imbedded mammae were also sectioned d o n g
the plane of the skin surface so that all hairs were cut in
cross-section. The numbers of hairs per given area wcre thcn
counted.
The estrogen applied topically was estradiol diluted with
sesame oil, which was used without estrogen as a control on
the left side of the two animals treated hy inunction.
Fcb. 18
Malc
I
+++ = reaction like that of pregnaut femalcs.
2.5 mg progesterone
5.0 ing progesterone
1 .0 m g estrogen
2.5 mg estrogen
Ang. 28
Oet. 97
0.025 mg cstrogen
1.0 mg estrogen
July 15
Male
Pe1nale
2.5 mg progesterone
5.0 mg progcsterone
Aug. 4
1.0 mg estrogen
10 I.U. estrogen rubbed
on right nipples
50 I.U. estrogen rubbed
on right nipples
0.1 mg estrogen
5.0 mg progesteronc
2.0 mg cstrogen
100 I.U. prolactin
0.3 mg progesterone
2.0 mg progesterone
on right nipples
0.025 mg estrogen
200 I.U. prolactin
300 I.U. prolactin
500 I.U. prolactin
50 I.U. cstrogen rubbed
Castrated
TREATMENT
Female
Oct. 19
Oct. 1
Nale
Aug. 11
Oct. 8
Femalc
195s)
Aug. 4
(811
DATIC OF
ESPERlMEXT
Male
SEX
1
5
1
2
9
1
4
5
8
5
10
9
13
1
1
7
5
4
16
1
4
3
3
-
NCMBEE OF
DAYS OF
TREATMENT
+++ *
ia
18
17
16
14
15
6
+++
+++
+++
+
+++
+
+++
-
14
-
-
-
-
+
DIDQRSIO OF
EQACTION
-
17
WCYBEE OF DAYS
AFTERSTAETOF
TBEATmNT
RBAOTION
BEFORE
~~.
FIEST NOTED
Trcatment and residts
TABLE
July 5, 1953
July 22, 1953
Bug. 19,1953
July 27, 1953
DATECASTBATED
F
B
=:
9
245
MAMMARY H A I R S O F APLODOKTIA
OBSERVATIONS
Exaniination of an extensive series of Aplodovztia collected
throughout the year indicated that there were varying degrees of development of mammary hairs in the wild population (fig. 1). The most pronounced condition in terms of
diameter of area affected and profuseness of black hairs was
observed in pregnant and lactating females. A less pronounced
condition was seen in females, both mature and yearling,
which had ovulated but were not pregnant. The faintest indication of the nipple area was on a juvenile female about 7
months old (fig. 3 ) and in certain adult males, where the
nipples wei-e barely indicated by a small area of dark hairs.
TABLE 2
Mean wadt11.s of approximately 100 “areolar” 71airsf 1’0111 clifferent rndivitlzials
CONDITION
AND SEX
Young male
ATulliparous yearling
female, probably post
ovulatory
Pregnant fenialc
Adult inale injected
with estrogcn
XIBAN W11)TH O F HAIRS
“Areolar”
Abdominal
microns
microns
14.2
18.0
22.8
29.0
13.5
13.5
31.0
16.0
The changes in mammary hairs were initiated prior to ovulation, since one female with tuba1 ova showed growing hair
follicles typical of the early stages of the injected animal.
Other females in the early stages of pregnancy showed changes
too profound to have occurred between ovulation and time of
capture.
In pregnant females the hair follicles of the “areolar”
area mere much larger than those of the juvenile or pearling
post-ovulatory, non-pregnant females (table 2 and fig. 4). I n
animals with actively growing mammary hairs, the mammary
gland tissue was hypertrophied and the lumina engorged.
Furthermore, sections cut through the periphery of the mam-
246
E. W. PFEIFFER
rnary tissue indicate that only the epidermis a i d its appciidages which overlie the mammary\- tissue show tlic c l i a i ~ itcre
istic reaction.
In the expcrinieiital animals (table 1) estrogen produced
in all cases except oiie a strongly positive iwxtioii identical
liistologically with that of early pregnant feiraales cauqlit iii
the wild. A positive reaction is defined as production of maniniary hairs that a r e qnantitatirely and qualitatively like tliose
found oii pregnant female;; just prior t o parturition. Thib
one exception was probably due to tEic v e i y l o ~ vdose administered to this aninial. Piginentation 1 x 7 ~ sfirst ohscrrcd iiiacroscopically about 10 to 16 days after the first injection.
Estrogen applied by inn~ictioii in very i r i i a l l ;amoiriit 5
produced noticeable pigmentation o n the estrogenized hide
at about the same time a s injected estrogen (fig. 2 ) . Soiiie
1)ignientation occurred later at the control iiipplcs t reate(\
with sesame oil, but this was thought t o result from a1)sori)tioii of small amomits of ehtvogeii through tlic skin into tlic
I)lood stream.
i t is posbiljlc that ~)rogeste~roiic
caused a slight rcactioii
in the February 18 esy)cii.iineiit (talile 1). The other two experiments with progo4teroiicA iiiust, howevei., be disregarded
hinec prior estrogen irijcction o r castration inade the results
iiivalid.
As part of the above esperiiiieiiti a 1iii:dl area of the :illcloiiicii of an intact, untreated, aiiesti-ous, young J’(~ni;~lc
\i
a\
shaoed to detcrniine if regrowth of hair x~~oulcl
l)i’otliice ti11
a r e a resemljlirig a positivci reaction. IIair was plucked fi.om
a siiiiilar area oil a cast i x t c d , eitrogen treated iiiiil~,hut i n
both areas regi-owth produccd hair that as i i i d i s t i i i ~ ~ ~ i ~ h n 1 , l c
froin that of the rc of the ahdoinen.
Treated animals or wild pregiimt femulcs h a r e thickoihairs around the nipplei than untreatrd (table 2 ) . Tlic incrcnse in hair sizc iii a saniple from trcatcd specinienq coultl
he brought about lip stirriiilatiiig the growth of new follicles
that produce larger hairs, l
q the molting of the smaller h i i - s
leaving oiily tlac larger hair around the inaimlac, o r by stimn-
M A M M A R Y HA41RS O F APLODONTIA
247
lation of existing follicles to grow larger, darker hairs. Since
counts of hairs per given area of treated and untreated specimens do not show a significant differelice in iiuniber f o r each
sex, and since histological study indicated that no follicle becomes atrophic and that n o new follicles a r e budded off either
the epidermis o r the existing follicle wall, it is assumed that
the existing follicles a r e stimulated to increased growth resulting in larger darker hairs.
A section of the niammary area of an untreated animal
(fig. 5) shows thin epidermis, a dense dcrniis and shallow,
thin follicles with papillary rests bciieath the bulbs of the
hairs. Little if any pigment is apparent in the hairs, and the
sebaceous glands a r e very small. I t should IN pointed out
here that Aplodopztia produces all abdomiiial hairs in groups
of 6 or more hairs per major follicle.
A few days after the first injections of estrogen, and in
estrous females, the nipples are hypertrophied, the epidermis
is now several cells thick, the dermis is thickened, and changes
have occurred in the hair follicles (fj:.
6). The hair 1I)~lbs
are n o w deep in the dermis, and the papillae ai-e in tlie h l b s
or matrices. Mitoses a r e evident, and much pigment is present
in the matrices around tlie papillae. The pigment is in both
the cortex and medulla of the newly foritied hairs, Init it is
absent or greatly reduced in the distal sectioiis of hair, which
represent growth that had occurred prior to treatment. Esamination of siinilar tissue a t a later time after tlie first estrogen injections reveals that the epideimis has again hecoine
thin, lout mitoses a r e still very common in the hair inalriccs
(fig. i). The sebaceous glands a r e swollcn, as is the external
root sheath of the hair follicle. Much pignicnt is distri1mtc.d
throughout the hair shafts from papillae to surface iiidicatiiiy
that all the old hair shafts have now passed out of the follicles.
DISCUSSION
Esperimental evidence indicates that estrogen is a key
agwt i n tlie production of mammarp hairs in laboratory
Aplodouticr, and my results ivitli cstrogeii, progcsterone, arid
248
E. W. PFEIFFER
prolactin a r e essentially the same as those obtained by Davis
et al. in 1945 (if one substitutes hair growth and pigmentation
for hypcrpignientation of the epidermis). However, the exact
inode of action of estrogen on the mammary epidermal tissues
of Aplodontia is unknown. It may act directly to stimulate
hypertrophy and/or hyperplasia of the epidermal, sebaceous,
a i d hair follicle cells, o r it may induce in mammary gland
cells the production of a substance which i n turn stimulates
the above tissue. Lastly, there may be a principle (e.g., prolactin) froni the pituitary or other gland which is elaborated
constantly by this gland arid will cause the reaction only when
the target tissue is potentiated by estrogen.
Any of these three alternatives could account for the unilateral reaction when estrogen is applied unilaterally. Hornever, there is evidence against the direct effect theory with
i*espect t o the hair follicles and melanoblasts. Thus, hair
growth and pigmentation continue for some days after estrogen has been withdrawn, suggesting that it has stimulated
production of a substance which then produces hair growth
and pigmentation. As indicated above, in several histological
preparations the reactive area of mammary skin almost exactly overlies the mammary tissue, suggesting that it may
be the source of the principle causing hypertrophy and hyperplasia. Transplant studies should resolve this problem. Cathcart et al. ( ’48) give a possible explanation for the limitation
of liyperpiffnientatioii. Having suggested an intimate relationship between the sympathetic plexus and the melanoblasts in the dermis, they state: “It may be that this profuse
innervation over the circumscribed area of the skin is the
determining factor in the limitation of the pigmentation of
pregnancy to this maniillo-areolar region. Alternatively it
may be that it is the skin sympathetic plexus of this area
alone which is closely associated with the underlying active
niaininary gland and its sympathetic plexus.”
With respect to the wild population, it was deterniined that
the reaction did not occur in fcinales unless some ovarian
activitv, a t least sufficient to produce uterine glandular pro-
MAMMARY HAIRS O F APLODONTIA
249
liferation, had occurred. This condition is best developed in
pregnant and lactating females in which estrogen is maintained at a high level f o r a long period of time, and it is
faintest in young females showing only slight follicular development. Thus, it is probable that the mammary hair reaction is a quantitative phenomenon, and that its degree of
development is correlated with the amount of ovarian and/or
placental activity (estrogen production). The slight reaction
in the castrated, untreated male which was intended as a
control may have been due to the action of estrogen from the
adrenals which are known to be a source of estrogen in some
mammals (Robson, ’47). It can, therefore, be postulated that
the epidermal area surrounding the nipples of A p l o d o ~ n t i ais
a special direct or indirect target area f o r estrogen. Assuming
this to be true, the question arises as to why these hair follicles
should respond to estrogen.
Bresslau (’20) in his book on the ontogeny and phylogeny
of the mammary apparatus, throws some light on the subject.
He describes the mammary glands of Afonotremata as consisting of individual tubes each of which opens at the base
of a long hair, the “mammary hair,’’ which probably serves
as a pathway for the mammary secretion. In the Rlarsupialia
only rudimentary mammary hairs are produced during the
ontogeny of the nipple, and they have a temporary existence
in most marsupials since nipples are developed. Recent workers (Fleay, ’54; Reynolds, ’EL?)have described significant
changes in the nipples and marsupia of certain marsupials
including new growth of hair in the marsupia of estrous
females. According to Rresslau it has been determined in
some species of placental mammals that the milk gland buds
arise in connection with rudimentary primordia of mammary
hairs, which never advance beyond the first stage of development. There is, however, an exception to this found in the
Sciuridae. Several squirrels have abdoniinal vibrissae, the
derivation of which Bresslau explains as follows: “. . . in
the accessory primordia of the squirrel the otherwise latent
capacity of producing mammary hairs comes into action,
250
E. W. PFEIFFER
while in compensation there is cessation of the development
of the milk glands. ’ ’
The recent experiments of Carlisle ( ’54) summarized above
indicate that certain lagomorphs also appear t o develop mammary tissue associated with hairs and their sebaceous glands.
This author concludes that if extra mamniary lobes are derived from hair follicles and sebaceous glands, “. . . it is
reasonable to suppose that the origin of all the mammary
lobes is from sebaceous glands with their ducts and the associated hair follicle, although doubtless the ontogeny has been
abbreviated and they normally develop directly. ”
This idea conflicts with the widespread belief that mammary
glands are derived from sweat glands.
In view of the above information and because Aqdodo?d icl
is closely related to the squirrels, it seems permissible t o
speculate that the mammary hairs iii ,IpZodoutin represent an
expression of the latent capacity of the mammary epidermal
tissue to produce special hairs associated with lactation, as
is found in the inonotrcnies. The production of mammary
hairs by the primitive ApZodoiztin may be a “physiological
relict” that has been lost by more advanced mammals. Thus,
in the higher rodents such as the guinea pig, and in primates,
such as man, the capacity of the areolar area to produce hairs
has been greatly reduced or lost, but the tissue still responds
to the ancestral hormonal pattern and produces pigmentation
of the epidermis instead of growth and pigmentation of hair.
This phenomenon in A p l o d o n f i n supports the belief that the
mainmary glands are derived from sebaceous glands mid n o t
sweat glands.
SUM;1PbR Y
Pregnant, lactating, and non-pregnant, post-ovulatoi*y females of a primitive rodent, Aplorloiztia m f c ( , exhihit dense
patches of black hairs around the nipples.
The integument arid its appendages in the area surrounding
the nipples were target organs of estrogen, alone o r in combination with other hormones. Estrogen directly or indirectly
thickened the epidermis of the nipple and surrounding area,
MAMMARY HAIRS O F APLODONTIA
251
and stimulated the hair follicles in this area to rapid growth
and hyperpigmentation resulting in hairs larger and darker
than before estrogen stimulation.
Various degrees of the reaction occur in the wild population,
with the degree of hair pigmentation and growth probably
depending on the amount of estrogen reaching the area and
the duration of estrogen stimulation.
Several possible modes of action of estrogen on the niammary epidermal tissue are considered and the phylogenetic
aspects of the mammary hairs are discussed.
ACKNOWLEDGMENTS
I wish t o thank Dr. 0. P. Pearsori and Dr. H. A. Bern, Dcpartment of Zoology, University of California at Berkeley,
and Dr. JV. R. Lyons, Division of Anatomy, University of
California School of lledicine, f o r their suggestions, advice,
and material assistance during the course of this work.
The progesterone (Proluton) and the estrogen (Progyrion
B) were generously supplied by the Schering Corporation.
L l T E R A T U R E CITET)
BAILEY,
R. E. 1952 The incubation patch of passerine birds. The Condor, 5 & :
121-136.
BRESSLAU,
E. 1920 The Mammary Apparatus of the Mam1n:ilia. Methueii Co.
Ltd., London.
CARLISLE,D. B. 1954 O n the relationship hetwern mammary, sweat, and sebaceous glands. Quart. J. Micro. Sci., 9.5 : p a r t I : 79-83.
CATHCART,
E. P., F. W. GAIRKSAND If. S.D. O ~ R V E N1948 The innervation of
the human quiescent nipple, with notes on pigmentation, erection, and
hyperneury. Trans. Roy. Soe. Edin., 6 1 : 699-717.
DAVIS,M. E., M. W. BOYNTOS,
J. H. FERGUSON
AXD R. ROTHhClN 1945 Studies
011 pigmentation of endocrine origin. J. Clin. Endocrinology, 5 : 138146.
FLEAY,
D. 1954 Australia’s pouched “cat.” Xatural Historv, 63: 86-92.
GALIGHER,A. E. 1934 The Essentials of Practical Microtrcliuique. A. E. Galigher, Inc., Berkeby.
HAMILTON,
J. B., Editor 1951 The growth, replacement, and types of hair.
Ann. K. Y . Acad. Sci., 5 3 : 463-751.
HOOKER,c. IT., AND c. A. PFEIFFER 1943 Effects of SEX horinones upon body
growth, skin, hair, and sebaceous glands in the rat. Endocrinology,
33: 69-76.
252
E. W. PFEIFFER
INGLE,
D. J. 1951 The functional interrelationship of the anterior pituitary
and the adrenal cortex. Ann. I n t . Med., 55: 652-672.
REYNOLDS,H. C. 1952 Studies on reproduction i n the opossum (Didelphis virginiana virginiana). Univ. Calif. Publ. Zool., 5 2 : 223-284.
ROBSON,J. M. 1947 Recent Advances i n Sex and Reproductive Physiology. The
Blakiston Co., Philadelphia.
STRUTHERS,
P. H. 1928 Breeding habits of the Canadian porcupine (Erethizon
dorsatum). J. Mammal., 9: 301-308.
TAYLOR,W. P. 1918 Revision of the rodent genus Aplodontia. Univ. Calif.
Publ. Zool., 1 7 : 435-505.
TUENER,C. W. 1939 The Comparative Anatomy of the Mammary Glands. University Cooperative Store, Columbia, Missouri.
WILKINS, L. 1950 Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. Charks C Thomas, Springfield.
AND J. DE VIT-4 1946 Local inhibition of
WILLIAMS, W. L., W. u. GARDNER
hair growth in dogs by percutaneous application of estrone. Endocrinology, 38: 368-375.
PLATE 1
ESPIANL3‘I’ION O F FIGURES
1 Left
- Anovulatory adult female.
Center - Fenlnle i n early pregnancy.
Right-Female about one month post partum. X 1/5.
2
Castrated adult male 22 days after start of estrogen inunction on right side.
The sesame oil produced depilation of the abdomen. X 1/5.
3
Uried “areolar” skin of juvenile female. Note sharp line where unreactive,
non-pigmented abdominal follicles begin. X 24.
4 Dried “areolar” skin of early pregnant female.
x
24.
PLATE 1
253
PLATE 2
EXPLANATION OF FIGURES
5 Nipple area of untreated intact male. X 29.
6
Nipple area of castrate male 15 days after first estrogen injection and 6 days
after final injection. X 29.
7
Nipple area of castrate adult female, 1 7 days after first estrogen injection
and 1 2 days after last injection. The sebaceous glands are smaller and the
epidermis thinner than in figure 6, but the hair follicles arc still growing
rapidly. X 70.
254
I1I.IRlJZARY HAIRS 03‘ APLODONTIA
E. W. PFEIFPER
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