Article Published in the Author Account of

Michael Sellix

Circadian Clocks in Mammalian Reproductive Physiology: Effects of the “Other” Biological Clock on Fertility

Abstract: As a discipline, chronobiology has come of age in the last 25 years. There has been an exponential increase in our understanding of the molecular mechanism underlying circadian rhythms of gene expression, physiology, and behavior. While the mammalian clock mechanism has not yet been fully described, most of the primary gears have probably been identified; however, there remains a large submerged portion of this physiological iceberg. What is the extent of "clock-controlled gene" expression in the myriad cell types in mammals? What are the cell specific physiological processes that depend either directly or indirectly on the clock? These questions remain largely unanswered, but recent advances suggest a substantial link between basic clock function and physiology in several systems. In the reproductive system, there has been a recent surge in research on molecular clock function in neuroendocrine and endocrine tissues. This makes sense a priori, given the established link between the circadian clock, behavior (including reproductive behavior), and endocrine physiology. By understanding the role of the clock in basic mammalian reproductive physiology, we can begin to explore its role in the onset and progression of diseases that negatively affect fertility. Advances in this area will certainly yield novel insights into the etiology of these disorders and may provide new and exciting avenues for clinical research in reproduction and fertility.



Introduction

Circadian rhythms are endogenous biological rhythms with periods near 24 hours (Welsh et al., 2010). These biological rhythms persist in constant environmental conditions but can be readily synchronized, or entrained, to the environment. Circadian rhythms are underlain, at the cellular level, by a molecular clock consisting of an autoregulatory transcriptional/translational negative feedback loop (for detailed reviews see Takahashi et al., 2008 and Welsh et al., 2010). At its core, the clock includes the transcriptional activators BMAL1 and CLOCK which heterodimerize and bind E-box sequence motifs in the promoter of target genes, including, but not limited to, the period (per 1-3) and cryptochrome genes (cry 1-2). Period (PER) and cryptochrome (CRY) undergo various post-translational modifications but eventually return to the nucleus and act as cyclic repressors of their own transcription by inhibiting the BMAL1:CLOCK complex. A combination of forward and reverse genetics has been used to define the contribution of each of these genes and their protein products to the timing of physiology and behavior (Takahashi et al., 2008). Mice carrying a dominant negative mutation of the clock gene, mutation or deletion of the per and cry genes, or a null deletion of bmal1 are either arrhythmic or have moderate to severe disruption of circadian rhythms of physiology and behavior.

Role of the Circadian Clock in Endocrine Physiology

Circadian rhythms of clock gene expression have been observed at the tissue and cellular level in a majority of endocrine tissues including the hypothalamus, pituitary, adrenal gland, thyroid gland, adipocytes, pancreas, and gonads (Prasai et al., 2011). The suprachiasmatic nucleus (SCN) of the hypothalamus is well established as the central circadian pacemaker (Moore and Eichler, 1972; Stephan and Zucker, 1972). Temporal cues from the environment synchronize the SCN which in turn signal downstream to neuroendocrine cells that control the timing of hormone secretion from peripheral endocrine organs (Hastings et al., 2007; Kriegsfeld and Silver, 2006). Evidence suggests that this neural timing system drives the rhythmic secretion of luteinizing hormone (LH) and subsequent ovulation (Everett and Sawyer, 1950; Everett et al., 1949). Lesions of the SCN have been shown to disrupt the timing of LH secretion, ovulation, and normal cycling in female rats (Wiegand and Terasawa, 1982; Wiegand et al., 1978). Though the pacemaker neurons in the SCN are necessary for normal rhythms of gonadotrophin secretion and ovulation, central clock gene expression is in no way restricted to this region (Guilding et al., 2009; Guilding et al., 2010; Guilding and Piggins, 2007). In fact, rhythms of clock gene expression have been recorded in multiple brain regions, including many of the hypothalamic and forebrain areas controlling the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes (Guilding et al., 2009). Circadian rhythms of clock gene expression have been observed in gonadotrophin releasing hormone (GnRH) neurons both in situ (Hickok and Tischkau, 2010; Zhao and Kriegsfeld, 2009) and in vitro using immortalized GnRH cell lines (Chappell et al., 2003). This growing body of work supports the notion that the coordinated timing of circadian clocks throughout the hypothalamus and forebrain may facilitate reproduction.

The pituitary gland is the earliest and best described of the circadian oscillators in the HPG axis (Bose and Boockfor, 2010; Buhr et al., 2010; Bur et al., 2010; Olcese et al., 2006; Resuehr et al., 2007; Resuehr et al., 2009). In lactotrophs CLOCK:BMAL1 heterodimers regulate prolactin gene expression through E-box mediated transactivation (Leclerc and Boockfor, 2005). GnRH appears to activate clock gene expression in gonadotrophs through the same intracellular mechanism used to drive LH gene expression (Resuehr et al., 2009). At this time there is no literature supporting a role for the circadian clock in cells that secrete adrenocorticotrophin, growth hormone, or thyroid stimulating hormone. However, given their rhythmic patterns of secretion it seems likely that the clock plays a role in their synthesis and secretion.

In addition to the pituitary, clock gene function has been examined in the adrenal gland (Nader et al., 2010), pancreas (Marcheva et al., 2010), and adipose tissue (Ando et al., 2009; Ando et al., 2005; Zvonic et al., 2006). Each of these endocrine tissues displays rhythmic physiological function that is likely to be timed by the molecular clock. Evidence suggests that the clock in the reproductive organs themselves can time events, such as the sensitivity to gonadotrophins and progesterone synthesis in the ovary and testosterone production in the testis (Alvarez et al., 2008; Boden and Kennaway, 2006; Kennaway, 2005; Mahoney, 2010; Sellix and Menaker, 2010). Clock gene expression has been described in the gonads and other reproductive organs (e.g., uterus) (Alvarez et al., 2003; 2008; Alvarez and Sehgal, 2005; He et al., 2006; 2007a; 2007b; Karman and Tischkau, 2006; Morse et al., 2003; Nakamura et al., 2010; Ratajczak et al., 2009; Yoshikawa et al., 2009) and altering circadian clock function has negative impacts on fertility (Boden et al., 2010; Kennaway et al., 2005; Ratajczak et al., 2009).

The Circadian Clock and Fertility: The Circadian Clock in the Testes

Clock control of testicular function is clearest in mammals in which reproduction is linked to daylength (photoperiodism) (Bartness and Goldman, 1989; Elliott et al., 1972; Goldman, 1999; Goldman, 2001; Menaker and Eskin, 1967). In mammals the control of photoperiod-dependent testicular growth and regression depends on the timing and duration of pineal melatonin secretion, itself regulated by the timing of activity in SCN neurons (Badura and Goldman, 1992; Bittman et al., 1991). Thus, the effects of photoperiod on testicular function are thought to be entirely independent of the circadian clock in the testes. Nonetheless, recent observations have highlighted a role for the molecular clock in testicular function.

Recent investigations have looked for circadian clocks in the mammalian testis (Alvarez et al., 2003; 2008; Alvarez and Sehgal, 2005; Bittman et al., 2003; Morse et al., 2003). Morse et al. (2003), using ribonuclease protection assay, did not detect a circadian rhythm of per1 or bmal1 gene expression in mouse testis. Further, these authors reported a non-circadian developmentally regulated pattern of per1 and clock gene expression in sperm, finding that per1 mRNA was elevated in spermatids relative to earlier (spermatogonia) and later (spermatocyte) stages of sperm development. Finally, they report that clock mRNA was not colocalized with per1 during development and they did not observe altered per1 expression in testes from dominant negative clock mutant mice.

These results were subsequently confirmed in two independent studies using male C57BL/6 mice (Alvarez et al., 2003) and BALB/c mice (Bittman et al., 2003). In addition to exploring the role of the clock in the testis, Alvarez and colleagues observed non-rhythmic clock gene expression in the thymus (Alvarez and Sehgal, 2005). Like the testes, the thymus contains primarily undifferentiated cells. These authors propose that the circadian clock is developmentally regulated so that it can be suppressed during differentiation in favor of a more critical “developmental” clock (Alvarez and Sehgal, 2005). Bittman and colleagues report variable, non-rhythmic per1 mRNA expression in seminiferous tubules from both BALB/c and C57BL/6 mice (Bittman et al., 2003). They observed per1 expression in seminiferous tubules (primarily spermatids and spermatocytes) and interstitial cells but did not detect per2 mRNA in either structure (Bittman et al., 2003). Additional studies continue to support the conclusion that a circadian oscillator dependent on the rhythmic expression of the canonical clock genes is not required for normal sperm development (Yamamoto et al., 2004).

While a role for the molecular clock in sperm development, motility, and fertilization capacity is unlikely, the clock may play a role in testicular androgen synthesis. Evidence from Alvarez and colleagues suggests that the circadian clock regulates fertility in male mice by controlling, in part, the level of steroidogenic enzymes in testicular Leydig cells (the primary testosterone secreting cell in the testes) (Alvarez et al., 2008). Mice that are homozygous null for the bmal1 allele (bmal1-/-) are infertile with significantly reduced sperm counts (70% reduction vs. wild-type) and hypomorphic seminal vesicles, though they display normal sperm motility and capacity for fertilization (as assessed by in vitro fertilization of wild-type oocytes). In addition, bmal1-/- mice had significantly lower testosterone and follicle-stimulating hormone (FSH) levels but considerably higher LH levels compared with wild-type littermates, suggesting a primary deficit in testosterone synthesis as well as other possible deficits in the HPG axis (Alvarez et al., 2008). Further, the expression of several steroidogenic enzymes (3-β-hydroxysteroid dehydrogenase, 17-α-hydroxylase) and the primary sterol carrier protein (steroidogenic acute regulatory protein; StAR) are reduced in testes recovered from bmal1-/- mice. Surprisingly, Alvarez and colleagues report a circadian rhythm of BMAL1 protein expression in both the cytoplasm and nucleus of Leydig cells, in contrast to previous studies that did not detect a circadian rhythms of per1 and per2 expression in interstitial tissue by in situ hybridization (Bittman et al., 2003) or per1 and bmal1 expression in whole testis RNA using ribonuclease protection assay (Morse et al., 2003). The discrepancies may have arisen from methodological issues related to the lack of cell-type specificity in these studies. Together, these data suggest that the circadian clock does not play a role in sperm motility and fertilization capacity, though it may have a function in normal spermatogenesis. Alvarez and colleagues provide the first evidence that the circadian clock in testicular Leydig cells may control the timing and amplitude of androgen synthesis and secretion from the mammalian testis. These data are noteworthy, given the diurnal rhythms of serum testosterone reported in mice (Lucas and Eleftheriou, 1980) and hamsters (Hoffmann and Nieschlag, 1977).

While it appears that clock genes play a role in testicular physiology, it is unclear to what extent these actions are dependent on the timing of the clock or are simply non-rhythmic functions of clock gene transcription factors. Is the timing of clock gene expression critical to spermatogenesis? Do additional non-canonical “clock” genes play an important role in this process? If bmal1 gene expression is rhythmic but per1 expression is not and per2 mRNA (in BALB/c mice; Bittman et al., 2003) is absent, one has to assume that the rhythmic activity of the clock in testicular Leydig cells depends on the activity of a presently unknown transcriptional repressor. What then is the novel “clock” gene that may substitute for per1 and per2 in the testes? Is PER3 the primary binding partner for the CRY proteins in Leydig cells?

The Circadian Clock and Fertility: Role of the Ovarian Clock

For as little as we truly know about the role of the circadian clock in testicular function, we know a good deal more about the circadian clock in the mammalian ovary (for a recent review see Sellix and Menaker, 2010). Circadian rhythms of clock gene expression have been observed in the ovaries of rats (Fahrenkrug et al., 2006; He et al., 2007a; 2007b; Karman and Tischkau, 2006; Yoshikawa et al., 2009), mice (Dolatshad et al., 2009; Johnson et al., 2002), and ruminants (ovine, bovine; Cushman et al., 2007). In rats, clock gene expression has been described in granulosa (GC), thecal (TC), and luteal (LC) cells (Fahrenkrug et al., 2006; He et al., 2007a; 2007b; Karman and Tischkau, 2006). Gene expression profiling indicates that in rat ovaries per1 and per2 mRNA expression peaks in the early night, persists when animals are placed in constant lighting conditions, and is not estrous cycle dependent (Fahrenkrug et al., 2006). Per1 and per2 expression was also observed in interstitial glandular tissue, corpora lutea, pre-antral, antral, and pre-ovulatory follicles (Fahrenkrug et al., 2006). In a report of the same year (Karman and Tischkau, 2006) circadian rhythms of per2 and bmal1 mRNA were observed in rat GCs and TCs.

These data do not provide definitive evidence for the existence of “cell autonomous” circadian oscillators, i.e., clock function in the cells independent of timing cues from the SCN, in the ovarian cells. Using bioluminescence monitoring of primary GC and LC cultures from per2-destabilized luciferase (per2-dLuc) transgenic rats, He and colleagues reported circadian rhythms of per2 expression in LCs from pregnant rats and immature rats primed with equine chorionic gonadotrophin (eCG) and human CG (He et al., 2007a). These data indicate that follicular cells are able to express cell autonomous circadian rhythmicity, and that these oscillators can be affected by gonadotrophins, though the effect depends on cellular differentiation (e.g., undifferentiated GCs vs. luteinized and differentiated LCs). Using period1-luciferase transgenic rats our laboratory recently examined the response of the circadian clock in GCs/TCs to phase-shifts of the 12:12 L:D cycle and found that entrainment requires humoral, but not neural, inputs (Yoshikawa et al., 2009). Circadian rhythms of per1-luciferase gene expression were measured in primary follicular cell cultures and we observed phase-dependent responses to LH or FSH treatment in these mixed cultures (Yoshikawa et al., 2009). These data suggest that the rat ovary contains gonadotrophin-sensitive, cell-autonomous circadian oscillators.

Interestingly, there are several parallels between data on the ovarian clock and results from the work on clock gene expression in the testis and thymus. Specifically, experiments that examined clock gene expression in immature and undifferentiated cells (immature follicles, immature sperm cells, thymus cells) found that they lack circadian clock gene expression, whereas more mature and differentiated tissues (pre-ovulatory follicular cells, luteal cells, testicular Leydig cells) display robust circadian clock function (Alvarez and Sehgal, 2005; Bittman et al., 2003; Karman and Tischkau, 2006). In both tissues, the circadian clock is found in those cells responsible for steroid hormone biosynthesis (ovary: granulosa, thecal and luteal cells; testis: Leydig cells (Alvarez et al., 2008; Fahrenkrug et al., 2006; He et al., 2007a; Karman and Tischkau, 2006). These data are in agreement with both prior research on ovarian clocks and the literature describing clock gene expression in developing sperm cells. Many important questions remain unanswered: (1) what is the molecular switch that controls the expression of the circadian clock during differentiation? (2) If the circadian clock is critical for the timing of cellular physiology, why silence it during differentiation? Perhaps suppressing the molecular clock, which depends on phosphorylation and ubiquitination reactions to oscillate, shifts energy needs to the more critical molecular processes of cellular differentiation. These questions are particularly relevant to the fields of oncology, developmental biology, and stem cell research.

These data suggest that the circadian clock in ovarian cells plays a role in timing of ovarian physiology; however, they do not provide evidence for a link between clock function and the timing of steroid hormone biosynthesis and/or ovulation. To investigate the physiological role of the clock in the rat ovary, our lab suppressed endogenous LH secretion with a selective gonadotrophin releasing hormone (GnRH) receptor antagonist (Cetrorelix; CET) and examined the phasic response of the ovary (i.e., ovulation) to exogenous gonadotrophin treatment (Sellix et al., 2010). Animals that were maintained in a 12:12 L:D cycle and treated with CET on the afternoon of diestrus or the early morning of proestrus displayed a robust diurnal rhythm of ovulation in response to exogenous LH-treatments such that animals ovulated more frequently and with greater oocyte production when injected during the dark phase. A repeat of this experiment with rats kept in constant dim light revealed an equally robust circadian rhythm of ovulation with a peak during the subjective night (defined by activity onset). We conclude that the circadian responsiveness of the ovary to LH, independent of the timing of endogenous gonadotrophin secretion, contributes to the timing of ovulation. We propose that this rhythm of sensitivity to LH is produced by the circadian clock in the ovary itself. However, given the presence of receptors for glucocorticoids, leptin, thyroid hormone, and melatonin in ovarian granulosa cells, we cannot rule out the possible participation of other rhythmic hormones. The potential influence of these hormones on the timing and/or amplitude of the rhythmic sensitivity to LH represents an exciting avenue for understanding the impact of disorders like chronic adrenal hyperplasia (CAH), Cushing’s disease, or primary hyperthyroidism/hypothyroidism on fertility.

Several recent studies describe the effects of disrupting circadian clock function on fertility (Boden et al., 2010; Boden and Kennaway, 2006; Dolatshad et al., 2006; Kennaway, 2005; Kennaway et al., 2005; Miller et al., 2004). Reduced fertility and fecundity have been reported in middle aged per1-/- and per2-/- mice (Pilorz and Steinlechner, 2008). Animals expressing the dominant negative clock mutation (clockΔ19) have prolonged estrous cycles with extended periods of estrus (Dolatshad et al., 2006; Miller et al., 2004). Evidence suggests that irregular estrous cycles in clock mutant mice are due to abnormal rhythms of vasopressin (AVP) expression in SCN neurons and reduced AVP1a receptor in SCN target regions in the hypothalamus (Miller et al., 2006). Impaired fertility and fecundity have been observed in bmal1-/- mice (Alvarez et al., 2008; Boden et al., 2010; Ratajczak et al., 2009). As in males, female bmal1-/- mice display abnormal steroidogenesis with reduced progesterone secretion from LCs (Ratajczak et al., 2009). This effect appears to result from reduced expression of steroidogenic acute regulatory protein (StAR) in LCs. Although bmal1-/- mice exhibit abnormally long estrous cycles, they produce viable and fertilizable ova (Ratajczak et al., 2009). Compared with wild-type littermates, these animals display a higher incidence of implantation failure due to reduced progesterone secretion from the corpus luteum (Ratajczak et al., 2009). It is worth noting that, unlike testicular Leydig cells, StAR and bmal1 are apparently not rhythmically expressed in corpora lutea, suggesting that regulation of steroidogenesis by bmal1 in the ovary may occur through a non-rhythmic, but still clock gene-dependent mechanism.

Hierarchal Neuroendocrine Control of Ovulation: A Timely Transition

The textbook explanation of the way in which ovulation is timed in rodents assumes a hierarchy in which the circadian oscillator in the SCN drives circadian rhythms of GnRH release, which in turn stimulates LH secretion on the afternoon of proestrus (Sellix and Menaker, 2010). This preovulatory surge of LH initiates a cascade of events leading to follicular rupture and oocyte release (Espey and Richards, 2002; Richards et al., 2002). Recently the situation has become more complex with the evidence that the GnRH neuron may be an autonomous circadian oscillator (Chappell et al., 2003; Gillespie et al., 2003; Hickok and Tischkau, 2010; Zhao and Kriegsfeld, 2009) and that clock gene expression is rhythmic in pituitary cells (Bose and Boockfor, 2010; Leclerc and Boockfor, 2005; Olcese et al., 2006; Resuehr et al., 2007; Resuehr et al., 2009). Together with the evidence presented here for the participation of circadian clock function in the gonads, these new findings suggest a re-orientation of the classic view. Rather than simply acting in response to temporal cues from the hypothalamus (specifically the SCN), processes like ovulation, sperm development, and steroid hormone synthesis are facilitated, and possibly even driven by, the interaction of synchronized autonomous circadian oscillators at each level of the HPG axis. Further, rhythms of hormone secretion from endocrine organs outside of the HPG axis may also play a substantial role in the timing of ovarian and testicular physiology by altering the timing and amplitude of testicular androgen secretion or the ovary’s rhythmic sensitivity to gonadotrophins.

The Circadian Clock and Fertility: Role of the Clock in Reproductive Disorders

Male reproductive disorders

There are currently no studies linking male reproductive disorders to the activity of the mammalian circadian clock. However, with the limited evidence acquired using rodent models we can postulate that conditions leading to reduced clock function and/or altered phase synchrony among the clocks of the HPG axis could result in a significant decline in male fertility. Increasing evidence suggests that the decrease in testicular androgen production associated with aging, referred to as andropause, leads to a significant decline in male fertility due to reduced sperm motility, reduced libido, and erectile dysfunction (Lambert et al., 2006; Pasqualotto et al., 2008). Given the link between circadian clock gene expression and androgen synthesis in Leydig cells, it is possible that the molecular clock plays a role in the aging-associated decline in testosterone production and thus fertility. This conjecture is supported by the fact that circadian rhythms show a dramatic and widespread decline in amplitude with age (Gibson et al., 2009).

Female reproductive disorders

Disrupting the circadian system affects fertility: jet-lag and shift-work

Several recent reviews have described our current understanding of the impact of rotating shift-work and jet-lag on fertility in women (Boden and Kennaway, 2006; Mahoney, 2010). Rotating shift-work schedules and chronic jet-lag are associated with an increased incidence of cardiovascular disease, breast cancer, stroke, compromised immune function, and reproductive or fertility disorders (Castanon-Cervantes et al., 2010; Harrington, 2010; Mahoney, 2010). Lack of synchronization among endogenous rhythms of sleep/wake, body temperature, and hormone secretion and the environment appears to be a significant root cause of shift-work and jet-lag effects (Harrington, 2010). Women that work evening shifts or rotating shifts often report altered menstrual cycles, increased bleeding, and heightened menstrual pain (Labyak et al., 2002). Altered reproductive function in these women is associated with changes in the duration of the follicular phase and the level of FSH secretion, suggesting that desynchrony among HPG oscillators caused by shift-work alters the timing and/or amplitude of pituitary hormone secretion (Chung et al., 2005; Lohstroh et al., 2003). It has been reported that flight attendants are more likely to have spontaneous abortion if they work during their pregnancy (Knutsson, 2003). It has also been suggested that lack of synchrony among central and peripheral circadian oscillators, probably due to differential rates of re-entrainment to a changing light cycle, is the primary cause of these adverse effects (Reddy et al., 2002). If our proposed model of the HPG axis as a circadian system of synchronized oscillators is accurate, we would expect that reduced synchrony among these oscillators would contribute to diminished fertility and fecundity in shift workers and/or those exposed to chronic jet-lag.

Polycystic ovarian syndrome: could excessive androgen secretion alter the clock?

Polycystic ovarian syndrome (PCOS) is a common and devastating disease effecting 5-10% of women. While the features of the disease are well known, the etiology of the disorder is largely a mystery (Xita and Tsatsoulis, 2006). The primary symptoms of PCOS include abnormal ovarian anatomy and physiology, specifically anovulation or oligoovulation and polycystic ovarian morphology (Dunaif, 1997; Ehrmann, 2005). PCOS is often co-morbid with a metabolic syndrome characterized by hyperinsulinemia, dyslipidemia, decreased insulin sensitivity, obesity, and increased risk of cardiovascular disease (Dunaif, 1997; Ehrmann, 2005). For most patients it is thought that excessive ovarian androgen secretion during development is an underlying cause of PCOS (Balen et al., 2009; Homburg, 2009; Padmanabhan et al., 2006). Might excess androgen secretion act to produce PCOS by altering the circadian clock? Recent evidence suggests that excessive androgen secretion could modulate circadian rhythms of physiology and behavior through direct effects on the central circadian clock in the SCN (Iwahana et al., 2008; Karatsoreos et al., 2007). Androgen receptors are present in SCN neurons and androgens are known to alter circadian rhythms of activity, body temperature, and hormone secretion, most likely by altering the timing or amplitude of clock gene expression in SCN neurons (Iwahana et al., 2008; Karatsoreos et al., 2007). Thus, it is possible that the excess androgen secretion common to PCOS patients modulates circadian clock function directly. Alternatively, abnormal clock gene expression in the ovary could affect the expression of steroid hormone biosynthetic enzymes, leading to excess androgen secretion and PCOS. Several rodent models of PCOS have been developed (Demissie et al., 2008; Manneras et al., 2007; Shi et al., 2009; Stener-Victorin et al., 2004). Using rodent models, it should be possible to explore the impact of excess androgen secretion, either prenatally or during adolescence, on the timing of the circadian clock in both central and peripheral oscillators of the HPG axis including GnRH neurons, pituitary gonadotrophs, and ovarian granulosa cells. It may be that the etiology of diseases like PCOS that dramatically reduce fertility could be explained by a significant loss of phase synchrony among the autonomous circadian clocks of the HPG axis.

Conclusions

By expanding our understanding of basic circadian clock function in the neuroendocrine and endocrine cells that comprise the HPG axis, we can begin to examine the role of the clock in common, complex, and devastating diseases that impact fertility. Circadian clocks, due primarily to their effects on steroid hormone biosynthesis, appear to play a role in reproductive physiology in both male and female mammals. The circadian clock in the testis is associated with androgen synthesis and sperm development. In females, circadian clocks are found in granulosa cells and luteal cells where they seem to play a role in both the timing of ovulation and progesterone secretion. In both sexes these are critical gonadal functions associated with normal reproductive physiology. The knowledge that circadian clocks are found at each level of the HPG axis, and in particular the gonads, leads us to hypothesize that successful fertility depends in part on synchronization among these oscillators. Altering this synchrony, either through the indirect effects of forced desynchrony in shift-work or repeated jet-lag or through direct influence on the timing of the clock by androgen excess and/or other endocrine pathophysiology, could have powerful and lasting negative impacts on fertility. Continued exploration of the impact of these conditions on the circadian clocks of the HPG axis should lead to better diagnosis and treatment of those fertility disorders to which circadian pathologies contribute.

Acknowledgments

The authors would like to thank Pinar Pezuk for insightful comments on the manuscript.

Disclosure

The authors report no conflicts of interest.

Corresponding Author

Michael Menaker, Ph.D., Department of Biology, University of Virginia, P.O. Box 400328, Charlottesville, Virginia 22904, USA.

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 11(59):273-281, April 2011.]

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