Factors associated with low progesterone concentrations and their

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ISRAEL JOURNAL OF
VETERINARY MEDICINE
FACTORS ASSOCIATED WITH LOW PROGESTERONE CONCENTRATIONS
AND THEIR RELATION TO LOW FERTILITY OF LACTATING DAIRY COWS
Wolfenson D.
Department of Animal Science, Faculty of Agriculture, the Hebrew University, Rehovot 76100, Israel
Introduction
In the last two decades our understanding of reproductive biology in cows has
increased significantly. This was made possible due to intensive use of methods such
as ultrasonography, in vitro maturation and fertilization of oocytes, gene expression
technology, and other techniques. However, despite these innovations, dairy cow
fertility did not improve over the years. Low fertility becomes a major limiting factor
in efficiently managed dairy farms in both developed and underdeveloped countries.
Several factors are associated with low fertility of the dairy cow; among them is the
low concentration of progesterone in the circulation (Santos et al., 2004). Low
progesterone may affect reproductive processes either before or after insemination.
The situation has been aggravated in recent years because achieving a continuous rise
in milk production is associated with a gradual decline in plasma progesterone
concentrations, consistent with the negative relationship between milk production and
progesterone concentration (Lucy et al., 2001). This relationship may be attributed to
accelerated progesterone metabolism in the liver.
Low concentrations of progesterone in the cycle preceding artificial insemination (AI)
have been associated with the persistent follicle syndrome, which has been shown to
involve higher than normal pulsatile LH secretion and early maturation of the oocyte
in the preovulatory follicle. Insemination following ovulation of persistent follicles
resulted in retarded embryos development (Revah and Butler, 1996). It has been
shown that the conception rates of cows inseminated following ovulation of a
persistent follicle were considerably lower than those in normal cows (Santos et al.,
2004).
Suboptimal luteal function after AI could be associated with either low secretion of
suboptimal amounts of progesterone or with early luteal regression. The latter
situation ultimately results in embryo death. The effect of low concentrations of
progesterone post AI on fertility is a controversial issue. Progesterone is essential for
the maintenance of pregnancy, however, according to Lucy (2001), the minimum
concentrations of progesterone required for maintaining pregnancy are not known.
Nevertheless, several studies show low progesterone concentrations to be associated
with low fertility. For example, Mann and Lamming (2001) showed that low plasma
progesterone concentrations and a delay in the rise of luteal phase progesterone postovulation were associated with retarded embryo growth and low secretion of
interferon-t on day 16 post AI. Retarded embryos on day 16 may eventually die, or
low interferon-t could lead to early luteal regression and secession of pregnancy.
Indeed, low progesterone has been shown to be associated with enhanced secretion of
PGF2a, which may induce luteolysis of the corpus luteum (CL) and termination of
pregnancy (Santos et al, 2004).
This minireview deals with three different aspects involving low progesterone
concentrations. The first aspect examined the effects of low preovulatory LH surge
concentration on CL growth and progesterone secretion. The second aspect examined
the debatable effect of summer heat stress on progesterone secretion. The third aspect
examined the consequences of the delayed effect of low progesterone concentrations
in one estrous cycle on PGF2a secretion in the subsequent cycle. The data presented
have been generated in our laboratory in recent years.
Preovulatory LH surge and post-ovulation progesterone concentrations
Preovulatory LH surge induces a chain of events in the ovulatory follicle that are
essential for the formation of a normally active CL. More specifically, LH surge
induces a sharp decline in the production of P-450 aromatase and a sharp increase in
the production of P-450-scc and 3b-HSD in the granulosa cells, resulting in a drop of
estradiol production and an increased production of progesterone in the ovulatory
follicle. The possible relation between low LH surge and the formation of suboptimal
CL has not been studied extensively. Low progesterone curves could result from low
LH surge, which could be associated with suboptimal luteinization of the growing CL,
following ovulation. Interestingly, this relationship was found in primates (ZelinskiWooten et al., 1997). Studies in cows (Ambrose et al., 1998) showed that an induced
low LH surge was associated with low post-ovulation plasma progesterone
concentrations.
To shed further light on these issues, we have studied the effect of different
preovulatory LH surge levels on progesterone curve and CL development following
ovulation (Less et al., 1998). Briefly, cyclic lactating Holstein cows were
synchronized. Following estrus, the presence of dominant follicles and CL was
verified by ultrasonography on day 7 of the cycle. The CL regressed following PGF2?
injection, and 40 h later, on day 9, the cows received a dose of hCG (5000 IU) or a
dose of GnRH analogue (Receptal, Buserelin) to induce LH surge. The doses were 2
µg, 4 µg, 8 µg (the recommended commercial dose),and 16 µg, or 2 injections of 8 µg
Buserelin given 90 min apart. Blood samples were taken frequently to characterize the
LH surge. Cows in all the treatments ovulated. The average LH duration was 4 h and
the LH surge peak ranged from 13 to 46 ng/ml. The peak value, the mean curve, and
the area under the LH surge curve were lower (P<0.05) in the 2-µg Buserelin dose
than in the other groups (Figure 1). In correlation with these data, the peak
progesterone value of the induced cycle was lower in the 2-µg Buserelin group than in
all other Buserelin-treated groups (Figure 2). The mean and the area under the curve
of progesterone were lower in the Buserelin groups than in the hCG group. Notably,
2x8 µg Buserelin treatment did not induce a wider LH surge, and the progesterone
curve was not different from that of 8-µg treatment. The CL diameter did not differ
between the groups. Importantly, this study showed that a low LH surge induced a
lower plasma progesterone profile, and that the hCG injection which maintains a
longer period of biological activity, induced a higher progesterone curve.
To support this in vivo finding, we (Less et al., 1998; Biger et al., 2000) examined the
steroidogenic capacity of granulosa and thecal cells exposed to different LH surges at
the beginning of luteinization. Luteinized granulosa cells exposed to low LH 'surge'
doses on day zero of culture, produced at the end of luteinization on day 8 of culture,
2.5 times less progesterone than cells exposed to high LH 'surges'. Similarly, lueinized
granulosa cells exposed to a long duration LH 'surge' on day zero of culture produced
more progesterone at the end of luteinization than cells exposed to a shorter LH
'surge'. Collectively, the above studies indicate that a preovulatory LH surge of
adequate size is required for the development of a fully functional CL.
Effect of chronic, summer heat stress on progesterone secretion
Suboptimal progesterone secretion is a possible cause of low fertility of dairy cows
during summer heat stress. This issue is controversial, however, and various studies
have found progesterone levels under heat stress to be higher, lower, or similar to
those under cool conditions (Wolfenson et al., 2000). The divergence among these
findings arises from the fact that most short-term, acute experiments did not
reproduce the responses obtained in long-term, chronic, seasonal studies.
Holstein cows in winter and in summer, at 60 to 80 days post-partum, yielding 49.0 ±
2.4 and 45.1 ± 2.2 kg milk/day, in winter and summer, were used in the study
(Wolfenson et al., 2002). Concentrations of plasma progesterone were significantly
higher in winter than in summer (Figure 3). No effects of milk yield or parity were
detected. Progesterone concentrations in the early days of the cycle were similar in
both seasons; however, during the mid-luteal phase they were 1.5 ng/ml higher, on
average, in winter than in summer (P < 0.05). To support the in vivo findings of a
higher progesterone curve in winter, we examined seasonal differences in
progesterone production by evaluating granulosa cells and thecal cells that were
collected from first wave dominant follicles and were luteinized in vitro during the
winter or summer. At the end of 9 days of luteinization, progesterone production by
luteinized granulosa cells was twice higher (P=0.10), and that of luteinized thecal
cells was three times higher (P<0.05) in winter than in summer. Importantly, the study
demonstrated that heat stress-induced damage to follicular function was carried over
to the subsequently formed CL, a damage that was noted in the granulosa-derived,
large luteal cells, but it was more pronounced in the thecal-derived, small luteal cells.
It was concluded that in most studies in which cows have been chronically heatstressed during the summer, the concentrations of progesterone decreased compared
with normothermic cows. In contrast, in most studies in which cows were acutely
exposed to severe heat stress (for example, solar radiation or very high temperatures
in environmental chambers), the progesterone concentrations either increased or
unaltered.
Delayed effect of low progesterone on PGF2a secretion on the subsequent cycle
It is well established that the episodic secretion of PGF2a, which induces luteolysis, is
controlled by oxytocin binding to its uterine endometrial receptors (Geisert et al.,
1994), and that progesterone controls the timing of the development of these oxytocin
receptors. Low progesterone concentrations post-insemination are thought to be
associated with high uterine secretion of PGF2a, which may interfere with pregnancy
recognition and result in embryo loss (Mann et al., 1999). However, low fertility in
cattle has also been shown to be related to low progesterone concentrations in the
cycle preceding insemination.
We investigated a possible delayed effect of low progesterone in one cycle on uterine
responsiveness to an oxytocin challenge, as expressed in PGF2a secretion in the
subsequent cycle (Shaham et al., 2001). We used untreated cows to represent high
progesterone treatment. These cows were compared with their counterparts, which
exhibited low and ascending plasma progesterone concentrations that were achieved
by manipulating endogenous progesterone secretion of the CL (Figure 4). Following
oxytocin challenge on day 16 of the subsequent cycle, 18 days after progesterone
treatments had ended, the increases in circulating PGF2a metabolite (PGFM)
concentrations in the low progesterone group were markedly higher than those in the
high progesterone group (Figure 5). The results indicate that low progesterone
concentrations during an estrous cycle have a delayed stimulatory effect on uterine
responsiveness to oxytocin during the late luteal phase of the subsequent cycle. The
resulting increase in PGF2a secretion may interfere with luteal maintenance during
the early stages of pregnancy.
Summary
Low progesterone secretion resulting from the formation of a suboptimal CL is a
major cause of low fertility of dairy cows. The two major causes of low fertility,
summer heat stress and negative energy balance, are associated with low progesterone
secretion. Nevertheless, the positive results in one study in which exogenous
progesterone was added, have not been confirmed in other studies. Thus, establishing
optimal hormonal treatment to improve fertility needs further systematic
experimentation.
Figure legends
Figure 1: Concentration of LH surges in plasma following the injection of different doses of GnRH
analogue (Buserelin) 40 h after PGF2a injection. The curve of the LH surge induced by 2 mg Buserelin
was lower (P<0.05).
Figure 2: Concentrations of plasma progesterone following ovulation induced by hCG or different
doses of GnRH analogue. The mid luteal phase level of progesterone was lower (P<0.05) in the curve
induced by the lowest GnRH dose (2 mg Buserelin) than in other treatments.
Figure 3: Plasma progesterone concentrations during the estrous cycle of cows in winter (•) were lower
(P<0.05) than those in the summer (°).
Figure 4: Plasma progesterone concentrations during (a) the treated oestrous cycle, when low and high
progesterone concentration curves were induced; (b) the subsequent cycle, when uterine oxytocin
challenge was induced on day 15 of the cycle. Untreated cows served as the high progesterone group
(D); low progesterone concentrations in cycle 1 were achieved by three consecutive injections of
PGF2a at 12-h intervals starting on day 3 of the cycle (D). Means DSEM.
Figure 5: Plasma concentrations of PGFM determined from 1 h before to 3 h after oxytocin challenge
(100 iu.; i.v. injection) on day 15 of the subsequent cycle, in cows exposed to high (D) or low (D)
progesterone concentrations in the previous cycle. Means ±SEM. P<0.05.
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