FSH and LH are glycoprotein dimers that are comprised of
FSH and LH, are glycoprotein dimers that are comprised of two subunits, a common α-subunit (αGSU) and a distinct β-subunit (FSHβ or LHβ, respectively), which determines the biological specificity of the gonadotropins (Ciccone and Kaiser, 2009, Gharib et al., 1990). The Bromoenol lactone of the gonadotropin subunit genes is also dependent on GnRH pulse frequency. In rat models, Fshb gene expression is preferentially stimulated at low GnRH pulse frequencies (maximal at an interval of every 120 min) (Haisenleder et al., 1991, Kaiser et al., 1997a, Kaiser et al., 1997b, Dalkin et al., 1989). Conversely, Lhb gene expression is preferentially stimulated at higher GnRH pulse frequencies (maximal at an interval of every 30 min) (Burger et al., 2008, Haisenleder et al., 2008). Expression of Cga, the gene encoding αGSU, is stimulated by both pulsatile and continuous GnRH, with less frequency dependence (Weiss et al., 1990, Ferris and Shupnik, 2006, Bedecarrats and Kaiser, 2003). The control of FSH and LH synthesis is closely correlated with the expression of the distinct β-subunits.
Many reproductive disorders are associated with disruption of GnRH, FSH, and/or LH signaling pathways (Seminara et al., 1998). For instance, persistently rapid GnRH pulses, which result in an increased LH:FSH ratio to contribute to excessive ovarian androgen production and ovulatory dysfunction, have been observed in polycystic ovarian syndrome (PCOS), a common disorder that affects 6%–10% of the female population of reproductive age (McCartney and Marshall, 2016, Dumesic et al., 2015). This syndrome is also associated with cardiometabolic abnormalities (Baldani et al., 2015), obesity, and impaired glucose tolerance (Wild et al., 2010, Blank et al., 2007). Conversely, low GnRH pulse frequencies and abnormal serum gonadotropin levels are associated with hypothalamic amenorrhea (Reame et al., 1985, Marshall et al., 2001). These examples highlight the importance of the proper functioning of HPG axis and of the differential control of FSH and LH secretion for normal reproductive function.
There are several excellent recent reviews of the signaling pathways activated by GnRH in the gonadotrope and of the regulation of gonadotropin subunit gene expression, but only a few focus on the differential regulation by GnRH pulse frequency (Thompson and Kaiser, 2014, Mugami et al., 2017, Thackray et al., 2010, Naor and Huhtaniemi, 2013, Coss, 2017, Stojilkovic et al., 2017). Several hypotheses regarding how gonadotropes decode patterns of pulsatile GnRH to differentially regulate FSH and LH production have been proposed. However, the exact mechanisms remain to be fully elucidated. This review focuses on the signaling pathways activated by different GnRH pulse frequencies to result in differential regulation of gonadotropin subunit gene expression. Studies using pulsatile GnRH in an effort to more closely emulate physiological responses of the pituitary form the basis of this review.
Experimental models for studying gonadotrope function Several experimental models have been used to study the hormonal regulation of the gonadotropes, including primary pituitary cell culture, in vivo animal models and immortalized cell culture. Primary cultures of mixed pituitary cells generated by dispersion of fresh pituitary tissue are frequently employed. However, several limitations of these models need to be mentioned. First, the anterior pituitary gland is a heterogeneous population of secretory cells including gonadotropes, thyrotropes, somatotropes, lactotropes and corticotropes, as well as folliculostellate cells, which each secrete distinct hormones. Gonadotropes represent only 10–15% of the adenohypophyseal cell populations (Ooi et al., 2004). Second, the gonadotropes and lactotropes are densely represented near the intermediate lobe in several species, suggesting a possible paracrine relationship (Bliss et al., 2010, Denef, 2008). Moreover, folliculostellate cells can affect experimental outcomes as they produce paracrine factors, such as follistatin and PACAP (Thackray et al., 2010, Kawakami et al., 2002, Winters and Moore, 2007), which can modulate gonadotrope responses. These paracrine relationships may be disrupted in dispersed pituitary cultures. Third, it is important to consider the endocrine environment at the time of pituitary harvest, such as the estrous stage of female mice, as these conditions may affect experimental results (Fallest and Schwartz, 1991).