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Chapter 34
Seasonal Regulation of Reproduction in
Mammals
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
FIGURE 34.1 Geophysical basis of seasonality. (A) The Earth’s axis of rotation is tilted at 23° relative to the
perpendicular of the plane of rotation around the Sun. The filled point represents a reference location at a high,
northern latitude. (B) This gives marked seasonal clines in the amplitude of annual day length variation from an
almost constant 12-h day in the equatorial regions to 24 h in the polar regions.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 34.2 Timing of the breeding season relative to gestation length. (A) Mammals generally time
parturition to coincide with relatively benign spring/summer conditions. This dictates the timing of the breeding
season, and hence small rodents with short gestations initiate pregnancy (P) during the summer months, while
long gestation ungulates like sheep and deer breed in the preceding autumn. (B) This is reflected in seasonal
patterns of testicular growth and regression in male Djungarian hamsters (top panel) and Soay rams (bottom
panel) exposed to natural illumination. Source: Adapted from Refs 1,2.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 34.3 Nutrition x photoperiod interactions controlling puberty in Suffolk lambs. Shown are the growth trajectories (gray
lines) for groups of lambs held on four different feeding regimes. The horizontal double arrows show the timing of puberty in each group.
The dashed curve shows the annual photoperiod cycle. Lambs fed from weaning on an ad libitum plane of nutrition grow to about 40 kg
by early autumn when they enter puberty. Delaying growth by undernutrition until the autumn or early winter leads to a delayed puberty
in the first winter of life, at a reduced body weight compared to ad libitum controls. If, however, growth is delayed by undernutrition until
the following spring, then puberty is not attained until the second autumn of life, when body weight is significantly higher than in control
lambs. Hence nutrition and photoperiod jointly determine the onset of reproductive maturation in lambs. Source: Redrawn from Ref. 7.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 34.4 Innate long-term regulation of reproductive activity in seasonal breeders and the synchronizing effect of
melatonin. (A) Ewes exposed to natural cycles of changing day length enter breeding condition synchronously in the autumn-to-winter
months. Pinealectomy (PX) removes the endogenous melatonin (M) signal and leads to asynchronous episodes of reproductive
activation (squiggles) and quiescence (straight lines). Synchrony can be restored by a subcutaneous infusion of melatonin in a temporal
pattern to imitate the endogenous sequence of nocturnal pineal melatonin signals spanning just a quarter of the overall annual cycle. A
sequence of infusions imitating the spring-to-summer photoperiod sequence is particularly effective as a circannual synchronizing
signal. (Source: Based on data in Ref. 10.) (B) Male adult Syrian hamsters exposed to a short photoperiod of 6 h light/18 h darkness for
25 weeks initially undergo testicular regression, reflecting reproductive quiescence. Afterwards, despite continued short day exposure,
they display a spontaneous recrudescence of testicular growth and return of reproductive activity. Source: Redrawn from Ref. 11.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 34.5 Maternal photoperiodic programming of reproductive development and endocrine function. (A) In Djungarian
hamsters, maternal exposure to different combinations of 12-h and 14-h photoperiods during gestation and postnatally leads to widely
different rates of gonadal growth (testis mass at 28 days). Additionally, exposure to a 14-h photoperiod during postnatal life promotes
more rapid gonadal development, if the prenatal photoperiod was 12 h rather than 14 h. Hence maternal photoperiodic history programs
photosensitivity in the neonate. (Source: Graph drawn based on data in Ref. 25.) (B) In Suffolk lambs, prolactin secretion shows a
similar history dependence. Exposure to an equinoctial photoperiod for the first 28 days of postnatal life suppresses prolactin secretion
in lambs born to mothers held on a 16-h photoperiod, but stimulates it in lambs born to mothers held on an 8-h photoperiod. Source:
Redrawn from Ref. 7.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 34.6 The photoneuroendocrine system drives the rhythmic release of melatonin. In mammals, light/dark information is
perceived by photoreceptors and retinal ganglion cells that project, via the retinohypothalamic tract (RHT), to the suprachiasmatic nuclei
of the hypothalamus (SCN), seat of the master circadian clock. In turn, the SCN controls the activity of the pineal gland (PG) via a
polysynaptic pathway running via the paraventricular nucleus of the hypothalamus (PVN), the intermediolateral cells of the spinal cord
(IML), and the superior cervical ganglia, whence noradrenergic neurons project massively to the pineal gland. The pathway is shown on
a schematic parasagittal section of rodent brain. The activity of the SCN restricts noradrenaline (NA) release and, consequently,
melatonin synthesis and secretion to the night time. The activity of the SCN is regulated by day length (photoperiod), and as a
consequence the duration of the nocturnal melatonin message changes seasonally: during summer, long photoperiods (LP) are
associated with short melatonin peaks, whereas during winter, short photoperiods (SP) are associated with longer melatonin peaks.
Source: modified from Ref. 51.
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FIGURE 34.7 The SCN encodes photoperiodic variation in day length. Photoperiod modulates rhythmic expression of multiple
genes in the Djungarian hamster SCN. The graphs show the 24-h expression profiles of clock and clock-controlled gene mRNA in the
hamster SCN. Animals were housed under long photoperiod (filled diamonds, solid line) or short photoperiod (open squares, dotted
line) for 8 weeks. Each value is mean ± SEM of four animals. Solid and open bars represent the dark and light periods, respectively.
Clock genes: Per1 = period 1, Cry1 = cryptochrome 1, Rev-erbα = nuclear receptor subfamily 1, group D, member1; clock-controlled
gene: AVP = argenine vasopressin. P-values represent interaction between Photoperiod and External Time (12.00 = mid light phase)
for each gene. Source: Modified from Ref. 58.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 34.8 Biochemical pathway of melatonin synthesis. Melatonin is synthesized from tryptophan, which is metabolized into
serotonin (5-HT) by tryptophan hydroxylase (TPOH) and aromatic amino acid decarboxylase (AAAD); serotonin is next acetylated into
N-acetyl serotonin (NAS), then methylated into melatonin by the consecutive action of the pineal-specific arylalkylamine N-acetyl
transferase (AA-NAT) and hydroxyindole-O-methyltransferase (HIOMT). Norepinephrine (NE) released at night binds to β1- and α1adrenergic receptors leading to a strong activation of a cAMP-dependent protein kinase A (PKA). PKA acts through multiple
biochemical pathways to promote melatonin synthesis. Notably, AANAT enzyme activity is strongly activated at night onset and
inhibited at night offset, determining the duration of the nocturnal synthesis of melatonin. Contrastingly, HIOMT activity shows only a
weak nocturnal induction but displays photoperiodic changes in activity with higher values in short photoperiod. This may modulate the
amplitude of nocturnal melatonin synthesis.
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FIGURE 34.9 Regulation of pineal AANAT gene expression in rodents and ungulates. (A) Radioactive in
situ hybridizations showing that Aanat mRNA levels are markedly increased at night in the rat pineal gland (top
panel), (Source: Adapted from Ref. 87.) whereas they are constitutively elevated in the sheep pineal gland
(bottom panel) (Source: Adapted from Ref. 88.); scale bars are 1 mm and 5 mm, respectively. (B) The differential
regulation in Aanat gene expression results in an earlier onset of melatonin synthesis and secretion at night
onset in ungulates (Source: Data here from the Soay sheep from Ref. 19.), where AANAT activity is regulated
posttranslationally, as compared to rodents. (Source: Data here in the Djungarian hamster, adapted from Ref.
89.)
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FIGURE 34.10 Timed melatonin infusion experiments demonstrate the importance of melatonin signal duration for
photoperiodic responses. (A) Mean paired testis mass measured in long day housed PX male Djungarian hamsters receiving
different daily durations of melatonin infusion. (Source: Adapted from Ref. 106.) (B) Mean serum LH concentrations in PX and
ovariectomized + estradiol-treated ewes treated daily with a short or long melatonin infusion. Prior to day 0, all PX ewes received a long
day melatonin infusion; beginning day 0, all ewes were transferred to short days and five ewes continued to receive the long day
melatonin pattern (О) while three were switched to a short day melatonin infusion (●). (Source: Adapted from Ref. 107.) Note that
whereas short day (long duration) melatonin infusions cause gonadal regression in hamsters, they promote reproductive activation in
sheep.
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FIGURE 34.11 The pars tuberalis (PT) expresses a high density of melatonin receptors. Staining for melatonin receptor
distribution in the sheep brain and pituitary gland. Left panel: autoradiography for high affinity melatonin binding sites in a parasagittal
section, using the radioanalog of melatonin 2-[125I]-iodomelatonin (IMEL). Note the intense labeling in the pituitary pars tuberalis (PT),
and lower levels of labeling in the hypothalamus (between the optic chiasm (OC) and the mammillary body (MB)), the cortex (C), and
the cerebellum (CB). (Source: Modified from Ref. 135.) Right panel: In situ hybridization for type 1 melatonin receptor (Mtnr1a) RNA
expression in coronal sections through the sheep hypothalamus. Note the intense labeling with the antisense (as) probe in the PT
region. Scale bar = 5 mm. Source: Images from Dr Hugues Dardente.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 34.12 Persistent photoperiodic control of prolactin secretion in hypothalamo-pituitary
disconnected (HPD) Soay rams. Intact and HPD rams were held on alternating photoperiod cycles of 16 weeks
16 h light/day (LP) and 8 h light/day (SP). In intact animals transfer to SP suppresses prolactin secretion and
activates FSH secretion. Remarkably, while HPD abolishes control of FSH, the seasonal photoperiodic control of
prolactin remains very similar to that seen in intact animals. See text for details. Source: Based on data in Ref.
172.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 34.13 Photoperiodic variation in α-glycoprotein–subunit (αGSU) and thyroid stimulating
hormone β–subunit (TSHβ) gene expression in the pars tuberalis of the European hamster. Under long
photoperiod (LP), high levels of expression of αGSU and TSHβ mRNA are observed. Under short photoperiod
(SP), expression of both genes is dramatically reduced. Scale bar = 200 μm Source: Adapted from Ref. 189.
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FIGURE 34.14 The role of thyroid hormone in seasonal breeding cycles in the sheep. (A) The normal seasonal profile of
luteinizing hormone (LH) secretion in estradiol-treated ovariectomized ewes comprises a phase of elevated expression commencing in
the autumn and continuing until early the following spring, when a pronounced decline occurs concurrent with the nonbreeding season
(N.B. data are plotted on a log scale, and levels during the summer months are below the sensitivity limit of the assay). (B) In
thyroidectomized (TX) ewes, thyroxine (T4) replacement permits the seasonal shut down of reproductive function, provided T4 is given
in the spring–mid-summer months. Delaying T4 replacement until the late summer–autumn months results in seasonal anoestrous
being abolished. Hence a sensitive spring–summer window for T4 actions is defined. Source: Adapted from Ref. 211.
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FIGURE 34.15 Anatomical localization of the seasonal reproductive effects of TH. (A) In the sheep, T4 microimplants placed in the
basal hypothalamus of THX ewes are sufficient to bring about seasonal breeding suppression during the spring. The diagram shows
hypothalamic locations in which implants were maximally effective. Abbreviations: AC anterior commissure, MB mammillary body, MT
medial thalamus, OC optic chiasm, PD pars distalis, PMH premammillary hypothalamus, PT pars tuberalis, VMH ventromedial
hypothalamus, vmPOA ventromedial preoptic area. (Source: Redrawn from Ref. 213.) (B) In the Djungarian hamster, T3-releasing
microimplants placed in the mediobasal hypothalamus override the inhibitory effects of short photoperiod on testis size. Asterisks in the
upper panel show the approximate location of bilaterally placed microimplants. ***Significantly reduced testis weight compared to
LD16:8 sham implant controls (P < 0.001). Source: Redrawn from Ref. 214.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 34.16 Thyroid hormone deiodination in the hypothalamus of a seasonal breeder. (A) Enzymatic pathways leading to the
conversion of thyroxine (T4) produced by the thyroid gland into either triiodothyronine (T3) by outer ring deiodination catalyzed by type 2
deiodinase (DIO2), or reverse T3 (rT3) by inner ring deiondination catalyzed by type 3 deiodinase (DIO3). The former, activating
process leads to increased thyroid hormone actions through nuclear thyroid hormone receptors; the latter is an inactivating process.
Further metabolism of T3 or rT3 is possible, leading to diiodothyronine (T2) production, which has no known signaling activity. (B)
Reciprocal switching between states of high Dio2/low Dio3 expression and vice versa, through photoperiodic control. Images are
autoradiograms of radioactive in situ hybridization histochemistry for Dio2 or Dio3 in coronal hypothalamic sections from sheep that
were held on either 8 h light/24 h (SP) or 16 h light/24 h (LP) for 4–8 weeks prior to sacrifice. Note strong labeling in the mediobasal
hypothalamic area under LP for Dio2, but under SP for Dio3; note also that Dio2 labeling extends into surrounding hypothalamic tissue,
while Dio3 labeling is confined to the ependymal zone immediately surrounding the third ventricle. Source: Adapted from Ref. 220.
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FIGURE 34.17 Central infusion of TSH promotes Dio2 expression in tanycytes surrounding the base of
the third ventricle. In the male Djungarian hamster, tanycytes express TSH receptors (TSHR, left panel) and
acute intracerebroventricular infusion of 1 mIU TSH (right panel), but not of Ringer solution (middle panel)
induces Dio2 mRNA expression within 4 h in short day-adapted animals. Scale bar = 100 μM Source: Adapted
from Ref. 237.
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FIGURE 34.18 Model for photoperiodic control of Eya3 and TSHβ expression in the pars tuberalis. The model proposes that
melatonin exerts a direct suppressive effect on Eya3 expression and an indirect effect via circadian gene oscillations in the pars
tuberalis. The phase of the circadian rhythm of Eya3 expression relative to the rhythmical presence of melatonin (Ψ) is critical for
determining whether a strong peak of Eya3 expression occurs. Independent of day length, Eya3 peaks some 12 h after dark (melatonin
onset). This means that under short days (SP, left panel), the peak occurs during the night, while the melatonin level is high and
exerting a suppressive effect, and so the peak is small. Contrastingly, under long days (LP, right panel), the Eya3 peak occurs the
following morning when the melatonin level is minimal, and so the peak is large. This classic ‘‘external coincidence timer’’ mechanism
limits EYA3/TEF synergism and hence elevated levels of TSHβ expression to long days, controlling the onset of a summer phenotype.
Source: Modified from Ref. 114.
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FIGURE 34.19 Kisspeptin (Kp) plays a key role in photoperiodic regulation of reproduction. (A) In the male Syrian hamster;
Upper panel, the number of Kiss1 mRNA–expressing neurons in the ARC is significantly increased in long photoperiod (LP) exposed
sexually active animals as compared to short photoperiod (SP) adapted animals; scale bar = 100 μM; (Source: Modified from Ref. 262.)
Lower panel, chronic (4 weeks) intracerebroventricular infusion of Kisspeptin 10 (Kp10, 1 mM, 0.25 μl/h) partially restores testicular
function in short photoperiod (SP)–adapted male Syrian hamsters. Note that Kp10-induced testicular activity is similar to that reached in
hamsters returned to LP for 4 weeks (LP return) (control = noninfused animals; aCSF = animals infused with artificial CSF). Bars with
differing letters differ significantly (p < 0.05); (Source: Adapted from Ref. 271.) (B) In the sheep; Upper panel, autoradiographs showing
elevated Kiss-1 expression at the level of the arcuate nucleus of female Soay sheep kept under short photoperiod compared to ewes on
long photoperiod (SP/LP, respectively); Scale bar = 1 mm; (Source: Adapted from Ref. 192.) Lower panel, patterns of secretion of
luteinizing hormone (LH) in individual anestrous ewes infused with Kp10 (15.2 nmol/h) for 24 h (infusion period is represented by the
black bars and arrows). Surges of LH secretion (in response to an increase in estradiol secretion stimulated by a rise in tonic LH)
occurred between 19 and 34 h after the start of the infusion of Kp10 Source: Adapted from Ref. 273.
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FIGURE 34.20 Photoperiodic regulation and role of RFRP 3 in the male Syrian hamster. (A) Autoradiographs
showing that Rfrp mRNA levels in the dorsomedial/ventromedial hypothalamus are markedly reduced in short
photoperiod (SP) as compared to long photoperiod (LP) conditions; Scale bar = 1 mm; (Source: Adapted from
Ref. 300.) (B) Acute intracerebroventricular administration of RFRP 3 induces a dose-dependent increase in LH
secretion within 30 min. Data are mean ± SEM (n = 7 per group) of circulating LH value examined 30 min after
the central injection (***, P < 0.001) Source: Adapted from Ref. 301.
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FIGURE 34.21 Working model for the pituitary/ hypothalamic network regulating seasonal reproduction in mammals. Photoperiodic
input is relayed to the PT via pineal production of melatonin and expression of type 1 melatonin receptors (MT1) in PT cells. Dependent
on the duration of the nocturnal melatonin signal, these cells produce high or low levels of TSH, which act on tanycytes surrounding the
base of the third ventricle (3v). High levels of TSH promote high levels of Dio2 expression in tanycytes, while low levels favor Dio3
expression. These enzymes determine the levels of T3 in the mediobasal hypothalamus. T4 is presumed to reach the ependymal region
via the CSF, although supply via brain capillaries (Cp) is not excluded. The resultant photoperiodic modulation of hypothalamic T3
levels in turn affects the activity of the neuropeptidergic neurons governing pulsatile GnRH release. This may include effects of T3 on
GnRH nerve terminals, or indirect effects via RF-amide neurons expressing Kp/RFRP. Resultant changes in pulsatile GnRH in turn
govern pars distalis (PD) gonadotropin secretion and hence reproductive output.
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