A host of secreted substances, that function in concert with hormones, govern reproduction; these compounds act either on contiguous cells within a restricted intercellular diffusion radius of their site of synthesis (paracrine regulators) or back on the same cell from which they were produced (autocrine regulators) (Figure 2-21). Metabolites of arachidonate, catecholamines, histamine, endogenous opioid peptides (EOPs), growth factors and cytokines generally fall into this category.
Eicosanoids. Arachidonic acid is the most abundant substrate for synthesis of eicosanoids. Arachidonate is made available to the organism either directly, as an essential component of the diet, or it can be synthesized within the liver from linoleic acid (prostanoids also can be synthesized from dihomo-g-linoleic acid [1-series] or eicosapentaenoic acid [3-series]); it is stored primarily in an esterified form within the phospholipid bilayer of cellular membranes.
Enzymes that transform arachidonic acid into eicosanoids are ubiquitous within the animal and plant kingdoms. The initial rate-limiting step in the arachidonic acid metabolic cascade is the enzymatic release of the fatty acid from membranes; this is accomplished by acyl hydrolases, such as phospholipases A2 or C. Phospholipase A2 releases arachidonate from the second glycerol carbon of phospholipids. Phospholipase C specifically cleaves inositol phosphate and diacylglycerol from phosphatidylinositol - a diglyceride lipase then liberates arachidonate from diacylglycerol. Only free arachidonate can be metabolized.
The two major pathways of metabolism of arachidonic acid that have been elucidated to date, cyclooxygenase and lipoxygenase, are outlined in Figure 2-22. The prostaglandins, prostacyclin, and thromboxanes are produced via the cyclooxygenase (prostaglandin endoperoxide synthase, PES) route. Many of the documented actions of NSAIDs have been attributed to inhibition of the cyclooxygenase function of PES. The more recently discovered leukotrienes and lipoxins are formed by the alternate action of lipoxygenases. A representative structure of each pathway is illustrated in Figure 2-23. A third route of metabolism involves the microsomal cytochrome P450-dependent mixed-function monooxygenases; little is known of the biological effects of products derived from this pathway.
Eicosanoids do not accumulate to any appreciable extent within cells, but are synthesized upon demand. A variety of chemical and mechanical stimuli can provoke eicosanoid release from cells. Eicosanoids are prone to peripheral degradation, predominately in the pulmonary circulation. A major fraction of intravenous prostaglandins are degraded in one pass through the lungs. The prostaglandins are converted enzymatically to inactive 15-keto metabolites, and then further catabolized by b and v oxidation. Polar catabolites are excreted in the urine and bile.
Most, if not all, tissues respond to eicosanoids. Seemingly insignificant changes in eicosanoid structure can manifest dramatic alterations in bioactivity. Eicosanoid receptors are highly selective. Very similar compounds can exert counteracting effects (eg., PGF2a causes vasoconstriction and PGE2 vasodilation; PGI2 inhibits and TXA2 stimulates platelet aggregation); homeostatic balance becomes compromised by unopposed production.
Prostaglandins are implicated in the regulation of ovarian functions, parturition, and secretion of gonadotropins. Most of the reproductive research attention has been centered on the stable prostaglandins of the E- and F-series; however, it is becoming apparent that other catabolites of arachidonic acid that participate in mechanisms of blood clotting (prostacyclin and thromboxanes) and immune/inflammatory reactions (leukotrienes and lipoxins) also play a role in reproductive processes.
Catecholamines and histamine. Catecholamines (dopamine, norepinephrine, and epinephrine) and histamine are monoamines derived from tyrosine and histidine, respectively (Figure 2-24); they appear to mediate steroid hormone actions on the GnRH-producing neuron (although little is known about the complex circuitry of such interactions). Biogenic compounds have also been implicated in the mediation of gonadotropic effects on the gonads. Histamine, a proinflammatory agent, is involved in the mechanics of implantation in some mammals.
Endogenous opiates. A group of very potent morphine-like substances (endorphins, enkephalins, and dynorphins) have been isolated from the brain (and other organs). Endogenous opiates are cleaved from larger precursor molecules (eg., proopiomelanocortin, POMC) after translation (Figure 2-25); they share a common four amino acid sequence (Tyr-Gly-Gly-Phe-), and like morphine and related narcotics, bind to the same family of receptors. Opiates inhibit neuronal conductance by suppressing entry of sodium ions across the axon. Naloxone is a drug that antagonizes the action of opiates.
Once believed to be involved mainly in perception of pain and its analgesic relief, EOPs are now known to influence reproduction. That morphine addicts are often infertile has been known for many years. Endogenous opiates (with adrenal hormones and prolactin) are elevated when an animal is physically or emotionally stressed; under conditions of persistent stress, this can lead to gonadal dysfunction. Stress imposed by nutrient deprivation in fasting and anorectic humans and underfed livestock and amenorrhea (failure to menstruate) and oligomenorrhea (scanty menstruation) among endurance-trained female athletes have been related to sustained production of EOPs (and small reserves of body fat). Amenorrhea due to fear of unwanted pregnancy is common among young women. Considerable evidence indicates that opiates (like barbiturates) inhibit secretion of gonadotropins, probably via an effect on the MBH. Other temporary states of diminished reproductive activity (seasonal, postpartum, and prepuberal) also appear to involve an inhibitory action of opiatergic neurons on the hypothalamus.
Growth factors and cytokines. Growth and development of tissues are controlled in part by local production of polypeptides known collectively as the growth factors; this group includes the transforming, epidermal, fibroblast, nerve, platelet-derived, and insulin-like and hepatocyte growth factors. Growth factors are produced by and act on a diversity of tissues - not limited to their namesake. Recent studies indicate that growth factors mediate various hormonal responses and cell-cell interactions within the gonads.
Cytokines are soluble peptides or glycoproteins released by cells of the immune system; this group includes the interleukins, interferons, and tumor necrosis, colony-stimulating, platelet-activating, and leukemia-inhibitory factors. Cytokines produced by activated T or B lymphocytes are called lymphokines. Cytokines produced by cells of macrophage lineage are called monokines. A bioactive acetylated glycerophospholipid, platelet-activating factor, is produced by granulocytes, mononuclear leukocytes, and many other tissues (eg., endothelium, embryo). Cells of the white blood series are common residents of reproductive tissues. The physiological relevance of cytokine actions within the reproductive system is a subject of current investigation. Some of the pleiotropic properties of growth factors and cytokines overlap (Table 2-4).