Principles and Practice of Endocrinology and Metabolism



Structure, Synthesis, and Storage of Gonadotropins

Subunit Composition

Carbohydrate Content

Control of Secretion of Gonadotropins

Pulsatile Activity

Controlling Factors

Effects of Luteinizing Hormone–Releasing Hormone on Gonadotropes
Therapeutic Usefulness of Luteinizing Hormone–Releasing Hormone

Pulsatile Versus Continuous Administration

Luteinizing Hormone–Releasing Hormone Agonists

Luteinizing Hormone–Releasing Hormone Antagonists

Gonadotropin-Releasing Hormone–Associated Peptide
Effects of Gonadal Hormones on Gonadotropins

Gonadal Steroids

Luteinizing Hormone and Follicle-Stimulating Hormone in Peripheral Blood


Gonadal Effects of Gonadotropins

Abnormalities of Gonadotropin Secretion and Action
Gonadotrope Adenomas of the Pituitary
Chapter References

The gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are large glycoproteins secreted from the anterior pituitary gland in response to hormonal signals from the brain and the gonads (Fig. 16-1). LH and FSH serve as intermediary messengers in the neuroendocrine system, which transmits environmental and central nervous system (CNS) information to the reproductive system. By transmitting the effects of exercise, diet, stress, and, in some species, of photoperiod and olfactory impulses, LH and FSH can stimulate ovarian and testicular function and therefore alter the physiology, fertility, and behavior of the host organism. In addition, pituitary gonadotropin secretion responds to hormonal signals returning from the gonads to allow integration of the function of the reproductive system, for example, during the menstrual cycle.

FIGURE 16-1. Schema for the control of gonadotropin secretion. (*Estrogen can be inhibitory or stimulatory to luteinizing hormone– releasing hormone [GnRH], depending on the level and duration of exposure, and perhaps other factors.) (¬, stimulatory;
, inhibitory; stim., stimulates; LH, luteinizing hormone; FSH, follicle-stimulating hormone.)

The a and b subunit structure of LH and FSH1,2 is similar to that of thyroid-stimulating hormone and human chorionic gonadotropin (hCG; see Chap. 15 and Chap. 112). Within each species, the a subunit is essentially identical in structure among the four hormones, whereas the b subunit differs among the four hormones and determines the biologic function of the dimeric molecule. The two subunits must be bound together through noncovalent interactions to be bioactive; neither has significant activity alone.
The approximate molecular mass of LH is 28 kDa and of FSH is 33 kDa; the a subunit common to both has a molecular mass of 14 kDa. These weights are approximate because of heterogeneity in the oligosaccharide (carbohydrate) moieties. The common a subunit has two N-linked carbohydrate side chains, LH-b has one, and FSH-b has two. Human chorionic gonadotropin-b has, in addition to two N-linked carbohydrate moieties, four O-linked moieties in its C-terminal 32-amino-acid extension. The exact structure of these carbohydrate side chains is unknown and variable, but they contribute ~16% of the weight of the LH molecule. The composition of the carbohydrate side chains of a given hormone shows a certain degree of microheterogeneity.3 The composition of these gonadotropin isoforms apparently varies according to the physiologic state and may, thus, determine the intrinsic bioactivity of the circulating gonadotropin at a given moment. However, the physiologic and pathophysiologic significance of this variability still remains unclear.
The sialic acid component of the carbohydrate side chain varies markedly in amount among the gonadotropins: 20 residues per molecule in hCG, 5 in FSH, and 1 or 2 in LH. The sialic acid content is directly related to the half-life of the hormone circulating in blood; hCG is cleared slowly, LH relatively rapidly, and FSH at an intermediate rate. In addition, the high degree of terminal sulfation of the carbohydrate termini in LH, as well as the rapid elimination of this type of glycoprotein through action of a specific liver receptor, contribute to the faster elimination rate of LH in comparison to FSH.4 Progressive desialylation of the gonadotropins shortens their half-lives and, therefore, decreases their bioactivity in vivo, whereas their in vitro bioactivity may be retained.5,6 Some of the deglycosylated hormones bind to receptors in vitro but do not stimulate adenylate cyclase, thereby functioning as competitive antagonists for the native hormone.7
The a and b subunits are products of separate genes for which the structures have been determined.8,9 A single gene encodes the a subunit for the four glycoprotein hormones. The amino acid sequence contains a leader or signal peptide that is removed before addition of the carbohydrate moieties (see Chap. 3).
An important advance has been the expression in cultured mammalian cells of complementary DNA (cDNA) for the gonadotropins.2 In mammalian cells, processing and glycosylation of the subunits, as well as combination and secretion, occurred in large quantities. In previously used bacterial cell systems, this had not been possible. The hormones produced by this recombinant technology are much purer than those obtained from human pituitaries or urine and can be produced in large quantities with constant quality. Significantly, they lack the postulated capability to transmit Creutzfeldt-Jakob disease, something which has halted the use of hormones prepared from human pituitaries10 (see Chap. 12 and Chap. 18). With this technology, one can also prepare gonadotropin analogs of different conformation and amino-acid or carbohydrate content, and test the structure and function relationships of these molecules, including possible antagonist compounds. Recombinant gonadotropins are now available for human LH, human FSH, and hCG.11 The availability of these agents facilitates greatly the care of patients with gonadotropin deficiencies and aids ovarian priming procedures involved in artificial reproductive techniques such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).
The cells that synthesize and store gonadotropins in the anterior pituitary, the gonadotropes, are distributed singly in acini made up largely of other cell types. Most gonadotropes stain with antibodies to both LH and FSH (or their b subunits), a finding that implies that the same cell produces both gonadotropins.12 A few cells stain for either LH or FSH, but not for both (see Chap. 11).
Because of its better supply and similarity in action to LH, hCG has generally been used in diagnostic testing and in therapy (see Chap. 93 and Chap. 97). Human menopausal gonadotropin (or menotropin), which is obtained from the urine of postmeno-pausal women, has an FSH-like and LH-like action; one preparation (Pergonal) has been used extensively to induce ovulation or spermatogenesis (see Chap. 97). Purified FSH and LH from urinary sources, as well as the recombinant form of FSH, are now available for clinical use.
The synthesis and secretion of LH and FSH are under the control of luteinizing hormone–releasing hormone (LHRH, also called gonadotropin-releasing hormone, GnRH), and gonadal steroids and peptides, including inhibin and activin (see Fig. 16-1). GnRH is a decapeptide that is a product of hypothalamic neurosecretion and is carried by the hypothalamico-hypophysial portal system to the gonadotropic cells of the anterior pituitary (Fig. 16-2). Binding of GnRH to receptors on the pituitary gonadotropes causes the release of both FSH and LH.

FIGURE 16-2. Amino-acid composition of luteinizing hormone–releasing hormone (GnRH) and some GnRH agonist analogs.

During embryonic life, the cell bodies of GnRH-secreting neurons are detected in the olfactory placode, from where they gradually migrate to their final locations in the hypothalamus. This migration of GnRH neurons is disturbed in the most common X-linked form of Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), due to mutation in an extracellular matrix protein, anosmin, and disturbance in development of the olfactory bulbs and tracts.13 Other forms of hypogonadotropic hypogonadism have been found to be due to inactivating mutations in the GnRH-receptor gene.14
After the embryonic migration period, cell bodies of GnRH neurons are found predominantly in two regions of the primate hypothalamus: (a) anteriorly, especially in the medial preoptic area and the interstitial nucleus of the stria terminalis, and (b) in the tuberal regions, particularly the arcuate nucleus and adjacent paraventricular nucleus (see Chap. 8).15,16 Physiologically important projections from these neurons go to the median eminence, where they terminate near the capillary bed of the portal system. Projections also are found to other CNS areas, such as the amygdala, hippocampus, and periaqueductal gray area, and to the posterior pituitary. The function of these projections is unknown, but the CNS projections could be important in the behavioral effects reported for GnRH. Stimulatory effects of GnRH on sexual behavior due to a direct CNS site of action have been reported in rodents.
GnRH is secreted in pulses that vary in frequency from approximately one per hour to as few as one or two per 24 hours. In sheep, direct measurement of GnRH in portal blood simultaneously with the measurement of LH in peripheral blood demonstrated that each LH pulse is preceded by a GnRH pulse.17
To generate pulsatile secretory activity, many GnRH neurons must be synchronized to secrete almost simultaneously. This synchronized neural activity can be recorded by electrodes placed in the hypothalamus and correlates with pulsatile increases of LH into the circulation.18 The neural mechanisms underlying this synchronous activity are not well understood (see Chap. 6).
GnRH secretory activity is affected by many CNS neurotrans-mitters and by gonadal steroids as well as other hormones. Opiates suppress gonadotropin secretion.19 This effect is almost certainly mediated through an effect on GnRH secretion, because little evidence exists that opiates exert a direct effect on pituitary responsiveness to GnRH in vitro. Opiate antagonists, such as naloxone, can stimulate LH secretion in humans, suggesting a significant tonic inhibitory effect of endogenous opiates on GnRH secretion.20 An important interaction occurs between the opiate effect and the prevailing steroid milieu, because naloxone administration increases LH levels in women in the late follicular and luteal phases but not in those in the early follicular phase or in postmenopausal women.20,21 In monkeys, little b-endorphin enters the portal blood during the early follicular phase or in ovariectomized animals.22 Levels of b-endorphin are markedly increased by estrogen and progesterone administration, a result that implies that these steroids may exert their inhibitory feedback effects partly through endogenous opiates.23 In men, similar mechanisms may occur, because testosterone markedly slows the frequency of pulsatile LH secretions, and opiate blockade inhibits this effect.24,25
Catecholamines that arise in central neurons probably are important in the control of GnRH, although relatively few data supporting this concept are available for humans. Available evidence suggests that, in general, norepinephrine is stimulatory to GnRH secretion, and dopamine may be inhibitory, but further work is necessary, particularly studies on the effects of different steroidal milieux.26 The roles of other neurotransmitters, including serotonin, g-aminobutyric acid, and epinephrine, in the physiology of GnRH secretion are even less clear. Prolactin and glucocorticoids may exert inhibitory effects.
Gonadal steroids exert profound effects on gonadotropin secretion; in many situations, whether these effects are exerted at a hypothalamic or a pituitary level is difficult to ascertain. However, a change in the frequency of pulsatile LH secretion is generally assumed to reflect an effect on the hypothalamus, because the frequency of LH pulses closely mimics that of GnRH pulses. In studies based on this assumption, progesterone has been demonstrated to have an inhibitory effect on GnRH, converting the normally rapid LH pulses of the follicular phase to the much slower frequency characteristic of the luteal phase.23 Similarly, testosterone administration leads to markedly slower LH pulse frequency in men, presumably through a hypothalamic effect.24 Estradiol exerts both inhibitory and stimulatory effects, depending on the level and duration of exposure.
GnRH plays a central role in the biology of reproduction. GnRH interacts with high-affinity receptors on gonadotrope cells of the anterior pituitary. The GnRH receptor belongs to the family of seven transmembrane domain receptors, interacting on ligand binding with Gq.27 This leads sequentially to activation of different phospholipases and release of free Ca2+ and lipid-derived molecules as second messengers.28 Activation of plasma membrane Ca2+ channels, mobilization of Ca2+ from intracellular stores, and activation of calmodulin-stimulated cell responses play an important role in GnRH action.29 In addition, the activation of phospholipase C (PL-C) is an early response, followed by those of phospholipase A-2 (PLA-2) and phospholipase D (PLD). Generation of second messengers inositol-1,4,5-triphosphate and diacyl-glycerol (DAG) mobilize intracellular pools of Ca2+ and activate protein kinase C (PKC). Both Ca2+-dependent conventional and CA2+ independent novel PK isoforms are activated during this process. Arachidonic acid (AA), liberated by activated PLA-2, also participates in PKC activation. Crosstalk between Ca2+, AA, and selected lipoxygenase products (e.g., leukotriene C4), and the different PKC isoforms might generate compartmentalized signal transduction cascades on GnRH stimulation of the gonadotrope-producing cells. These include the mitogen-activated protein kinase (MAPK) cascade. Activation of c-jun and c-fos by GnRH stimulation can participate in transcriptional regulation through formation of the transcription factor AP-1. At least partly dissimilar signal transduction systems mediate the GnRH-stimulated acute secretion of gonadotropins and the more prolonged stimulation of new gonadotropin synthesis.
The events previously described lead to changes in intracellular protein kinase levels that are thought to be important in stimulating gonadotropin secretion and synthesis, although the detailed mechanisms of these stimulatory effects are unknown (see Chap. 4). Gonadotropin synthesis occurs through the classic process of ribosomal formation of peptide chains, followed by posttranslational modifications in the endoplasmic reticulum and Golgi apparatus (see Chap. 3). These modifications include cleavage of segments off the amino terminus of both the a and b subunits and the subsequent addition of carbohydrate moieties to form the mature gonadotropin molecules in the secretory granules. After synthesis and storage in granules, gonadotropins are available for release almost immediately after GnRH stimulation. After exocytosis, the gonadotropins diffuse rapidly into the nearby capillaries and appear in the venous effluent of the pituitary.
GnRH and its agonist analogs are important in the treatment of GnRH deficiency states, including menstrual and fertility disorders in women (see Chap. 96 and Chap. 97) and hypothalamic causes of hypogonadism in men, such as Kallmann syndrome (see Chap. 115). However, GnRH infusion tests rarely give diagnostic information beyond that obtainable by measuring basal gonadotropin and gonadal steroid levels.
Gonadotropin secretion does not follow the GnRH input signal exactly, particularly when GnRH is administered in a nonphysiologic pattern. Soon after GnRH became available for experimental use, researchers noted that continuous administration of this hormone (e.g., by constant intravenous infusion) did not lead to constant LH output but rather to a biphasic pattern of increase, implying that two pools of releasable hormone existed.31 After the maximal response, a decline was seen in LH responsiveness that could not be explained by gonadal inhibitory feedback.32 Pulsatile administration of GnRH was observed to cause persistent pulsatile secretion of LH, whereas continuous GnRH infusion caused a desensitization of pituitary responsiveness.33 Continuous high-dose administration of GnRH over several days leads to almost complete failure of the ability of the pituitary to respond to GnRH secreted endogenously, yielding an experimentally induced hypogonadotropic hypogonadal state.34
The ability of continuous GnRH administration to inhibit pituitary gonadotropin production has been expanded greatly with the use of GnRH agonists (see Fig. 16-2).35 Once-daily administration of the agonist analogs results in several days of increased gonadotropin secretion, followed by desensitization and a hypogonadotropic state with very low levels of gonadotropin and gonadal steroid production, or “medical castration.” Such agonists have proved useful36 in the treatment of many conditions, such as prostate cancer (Chap. 225), endometriosis (Chap. 98), precocious puberty (Chap. 92), uterine leiomyomas,37 breast cancer, polycystic ovarian disease, cyclic porphyria, and acne, and for ovulation suppression and in vitro fertilization. Potentially useful applications include male contraception and the treatment of benign prostatic hypertrophy.
Antagonist analogs of GnRH are undergoing active development.35 These substances bind to GnRH receptors in the pituitary without stimulating gonadotropin secretion and block the effect of endogenous GnRH. Unlike GnRH agonists, they are immediately inhibitory, a potential advantage in the treatment of hormonally dependent conditions, such as prostate cancer. Antagonists may also prove superior to agonists in situations in which total gonadotropin inhibition is required, such as male contraceptive development, because even low levels of LH and FSH can partially support spermatogenesis.38,39 In nonhuman primate studies, the administration of an GnRH antagonist, together with physiologic replacement dosages of testosterone (because the animals would otherwise be androgen deficient), reliably eliminates spermatogenesis.40 Because the suppressive effect of the antagonist appears fully reversible, this combination shows promise for male contraceptive development (see Chap. 123).
GnRH (i.e., gonadotropin-releasing hormone) is synthesized in the hypothalamus as a part of a larger peptide, which is cleaved to yield GnRH and a larger fragment called gonadotropin-releasing hormone–associated peptide.41 Some reports have demonstrated that this peptide stimulates secretion of gonadotropin, particularly FSH, from pituitary cells in vitro and inhibits prolactin secretion. The physiologic role of this peptide remains to be explored, however.
Gonadal steroids and proteins exert direct pituitary effects on gonadotropin secretion along with their effects on GnRH secretion. Estradiol, for example, exerts both negative and positive feedback effects directly on the pituitary. Testosterone administration inhibits LH and FSH secretion by a direct pituitary effect in men.42 This effect is mediated in part by aromatization of testosterone to estradiol in vivo. Progesterone and testosterone also exert direct pituitary effects when studied in vitro, although these steroids have not been studied as definitively in vivo as has estradiol.
The major protein hormone product of the gonads is inhibin, a substance that has been studied for over 50 years,43 and now has been characterized structurally.44,45 Two 32-kDa forms of the glycoprotein, termed inhibin A and inhibin B and containing a and b subunits, have been described. Inhibin inhibits pituitary FSH secretion selectively, although at high levels it may also inhibit LH. Inhibin is produced in the Sertoli cells of the testis and in granulosa cells of the ovary, mainly under the stimulatory influence of FSH46,54
The structure of inhibin bears an interesting homology to that of other substances such as transforming growth factor and antimüllerian hormone.44,47 Antimüllerian hormone, also a product of Sertoli cells, leads to regression of the müllerian duct in the male embryo. Interestingly, alternative combinations of the subunits of inhibin (b-b instead of a-b) exert stimulatory effects on FSH secretion in vitro rather than the inhibitory effect of the inhibin molecule.48,49 These b-b combinations are called activins. Whether or not activins are secreted from the gonads, and what their effects might be in vivo, are areas of current research activity. Surprisingly, one of the activins stimulates hemoglobin production in human bone marrow in vitro.50 Many other effects of this family of substances have been described, including stimulation of early embryonic development and immunologic alterations. Follistatin, another protein produced by the gonads, also inhibits FSH secretion in primates.51 The precise roles of inhibins, activins, and follistatin in the control of gonadotropin secretion are active areas of investigation.
In women, inhibin A is elevated in the luteal phase of the menstrual cycle, whereas inhibin B is elevated in the follicular phase.52 Levels of both decline with age, implying a decrease in the quality of the remaining ovarian follicles. Inhibin B provides feedback inhibition of FSH, and a fall in inhibin B pre-dates the oligomenorrhea and increases in FSH that signal menopause. In men, inhibin B is the physiologically important form of inhibin.53 It exhibits a reciprocal relationship with FSH and a diurnal rhythm that appears to be independent of FSH or testosterone feedback.54
LH and FSH circulate in blood predominantly in the monomeric form found in the pituitary gland; little evidence exists for prehormones or smaller active fragments. However, changes in properties, such as the ratio of bioactivity to immunoactivity, have been reported in various states of aging, steroid environments, and GnRH analog administration. Some of these changes are apparently due to inaccuracies in determination of gonadotropin immunoreactivity.55 In monkeys, ovariectomy leads to a slight increase in molecular size and a decrease in the clearance rate of LH and FSH, which can be reversed by estrogen treatment. In aging men, the ratios of bioactivity to immunoactivity for both LH and FSH decrease.56,57 During GnRH antagonist administration, FSH bioactivity decreases much more quickly than does immunoactivity. This phenomenon has been explained by the demonstration of FSH isoforms in human serum that block the bioeffect of FSH on the gonads.58 Apparently, the secretion of these isoforms is stimulated by the GnRH antagonist. In all these situations, the conventional radioimmunoassays yield inaccurate assessments of the level of bioactive gonadotropins in blood. This error can be usually eliminated by use of two-site immunoassays.
The gonadotropins are cleared from the blood by both the kidney and the liver. Small amounts are also bound to the gonads, but this accounts for little of the hormone clearance. Some 10% to 20% of the hormone appears in a bioactive form in urine; most is metabolized in the hepatic and renal parenchyma. The half-life of FSH (4 to 5 hours) is much longer than that of LH (30 to 60 minutes); this is due partly to the higher sialic acid content of FSH, which impairs clearance, particularly by the liver, and partly to the high proportion of sulfated carbohydrate termini in LH, which accelerates its hepatic clearance.4
After the classical in vivo bioassays, the preferred method of gonadotropin measurements used to be radioimmunoassay using polyclonal antiserum. These assays now appear suboptimal due to their low sensitivity and poor specificity; in particular, they are unable to distinguish between low-normal and low levels. The second generation of immunoassays, using the non-competitive immunometric principle and nonradioactive signaling systems (enzyme, fluorescence, chemiluminescence) are superior in terms of sensitivity and specificity. Gonadotropin concentrations are expressed in terms of partially purified preparations of pituitary or urinary hormones. The use of standards of different purity, and various antisera, leads to different reference ranges reported by individual laboratories and makes their comparisons difficult. This problem will be partly overcome when recombinant gonadotropins are adopted as standards. However, the gonadotropin patterns during physiologic changes, such as aging (see Chap. 199), puberty (see Chap. 91), pregnancy (see Chap. 112), and the menstrual cycle (see Chap. 95), as well as in pathologic conditions, are similar in reports from various laboratories. Most of the antibodies used in LH assays cross-react with hCG, so that LH measurements are artifactually elevated when hCG levels in serum are high, as in pregnancy and choriocarcinoma (see Chap. 111 and Chap. 112). The possible presence of a common genetic variant of LH59 should be kept in mind, because some commonly used immunoassay methods do not detect this structurally aberrant form of LH.
Sensitive, specific bioassays are now available for the measurement of both LH and FSH in human serum. More time-consuming and difficult to perform than immunoassays, these bioassays are not in common clinical use. In general, bioassays have confirmed the conclusions obtained with immunoassays. Some discrepancies are found, however (see above), and bioassay analysis is indicated when the immunoassay result does not fit the clinical picture.
The only known bioeffects of LH and FSH are in the gonads. LH and FSH stimulate cell growth and maintenance in both the testis and ovary (see Chap. 94 and Chap. 113). As classically defined, LH stimulates steroidogenesis in both sexes, particularly testosterone synthesis, from Leydig cells in the male and from theca cells in the female. FSH stimulates spermatogenesis in the male and follicular development and estradiol secretion in the female. LH also induces ovulation from the mature follicle in the female and exerts a partial stimulatory effect on spermatogenesis in the male, probably mediated through increases in intratesticular levels of testosterone. LH and FSH were named for their initially described roles in females.
Both gonadotropins act through classic protein hormone–receptor mechanisms, involving a G protein–associated seven-transmembrane domain receptor.60,61,62 After ligand binding, adenylate cyclase is activated, leading to increases in intracellular cyclic adenosine monophosphate (cAMP), which is the main second messenger involved in gonadotropin action. The cAMP activates protein kinase, and the resulting protein phosphorylation is thought to be important in the cellular effects of the gonadotropins.
In the testis, LH directly stimulates the synthesis of a steroidogenic acute regulatory (StAR) protein, which plays a key role in the transfer of cholesterol from the outer to the inner mitochondrial membrane. This is the site of the first step in steroid hormone biosynthesis from cholesterol to pregnenolone. Thereafter, the metabolic steps in the steroidogenic pathway leading to testosterone take place in the smooth endoplasmic reticulum. Testosterone exerts stimulatory effects on Sertoli cells and on spermatogenesis39 (see Chap. 113). In men, this effect is probably mediated through the stimulatory effect of LH on intratesticular testosterone levels, because LH has no known direct effect on the seminiferous epithelium.
FSH binds to Sertoli cell and spermatogonial membranes in the testis. FSH is the major stimulator of seminiferous tubule growth during development. Because the tubules account for ~80% of the volume of the testis, FSH is of major importance in determining testicular size. FSH is important in the initial maturation of spermatogenesis during puberty; however, adult men can maintain sperm production despite very low blood levels of FSH if LH levels are normal.39 The total numbers of sperm produced in the absence of FSH are low. Normalization of FSH levels leads to quantitatively normal sperm production.63 These findings imply that the major physiologic role of FSH in men is to stimulate quantitatively normal levels of spermatogenesis.
Additional descriptions of ovarian and testicular effects of gonadotropins are presented in Chapter 90, Chapter 91, Chapter 94, Chapter 95 and Chapter 113.
An outline of the causes of gonadotropin abnormalities is presented in Table 16-1. Other aspects of the pathophysiology of gonadotropins, as well as detailed discussions of the etiologies, diagnosis, and treatment of gonadotropin abnormalities, are included in Chapter 17, Chapter 92, Chapter 96, Chapter 97, Chapter 103, Chapter 114, Chapter 115. Pituitary tumors that produce gonadotropins are discussed below.

TABLE 16-1. Abnormalities of Gonadotropins

Genetic studies have detected several mutations in the gonadotropin and gonadotropin-receptor genes. The ligand mutations are exclusively of the loss-of-function type, whereas both loss- and gain-of-function mutations have been discovered in the receptor genes. In the latter, the signal transduction system of the receptor is partially activated in the absence of ligand hormone, resulting in constitutive activation of the hormonal effects. These mutations have been very educational in terms of unraveling certain details of the physiology of gonadotropin action as well as the pathogenesis of certain disorders of reproductive function. Mutations in the FSH and LH b-subunit genes are extremely rare, probably due to the key role of these hormones in regulation of reproduction; no a-subunit mutations have so far been described. An inactivating LH-b mutation was found to cause absence of Leydig cells, lack of spontaneous puberty, and infertility in a male with normal early sexual differentiation.64 Two females with homozygous mutations of the FSH-b gene have been described in the literature.65,66 They both had primary amenorrhea with poor development of secondary sexual characteristics. One azoospermic male with similar mutations in the FSH-b gene has been described.67 However, he may have suffered from an additional unrelated disturbance of Leydig cell function, because his testosterone level was low, and his LH level was high.
Inactivating LH-receptor mutations67,68 and 69 in genetic males cause pseudohermaphroditism with severe Leydig cell hypoplasia, a finding that indicates a crucial role for the LH receptor in the stimulation of fetal testicular testosterone production and male sexual differentiation. In females, the phenotype of these mutations is anovulatory infertility and hypoestrogenism.69,70
An inactivating mutation in the FSH-receptor gene, an Ala® Val point mutation at position 198, has been detected in the extracellular domain of the receptor.71 The homozygous females have hypergonadotropic primary or early-onset secondary amenorrhea with arrest of follicular development, a diagnosis often termed resistant ovary syndrome. The male phenotype was surprising, because only variable oligoasthenozoospermia was found in these normally masculinized men, but no azoospermia or complete infertility.72 This indicates that FSH action is not an absolute requirement for the pubertal initiation and maintenance of spermatogenesis or fertility. However, qualitatively and quantitatively normal spermatogenesis appears to be dependent on FSH action. Partially inactivating mutations of the FSH-receptor gene have been described; the phenotype of these individuals includes secondary amenorrhea, high circulating gonadotropin levels, and arrest of follicular growth at the early antral stage,73 similar to that of patients with completely inactivating mutations. The role of FSH in ovarian and testicular function as indicated by the inactivating FSH ligand and receptor mutations is corroborated by very similar phenotypes observed in FSH-b74 and FSH-receptor75 knock-out mice.
Also, constitutively activating mutations are known for the LH and FSH-receptor genes. The former results in the familial male-limited, gonadotropin-independent, precocious puberty, “testotoxicosis.”76,77 The constitutive activity of the LH-receptor results in onset of testicular testosterone synthesis without LH action. No phenotype has been described in women affected with activation of LH-receptor mutations, apparently because premature LH activation has no effects on ovarian function without previous FSH priming, or because the prepubertal ovary does not express the LH receptor.
One case of a possible activating FSH-receptor mutation has been described in a male.78 The subject was a male who had been hypophysectomized due to pituitary adenoma. Despite unmeasurable gonadotropin levels, he had persistently normal spermatogenesis. A mutation was found in his FSH-receptor gene, resulting in marginal constitutive activation of the FSH-receptor and probably in maintenance of spermatogenesis in the absence of FSH.
Many pituitary adenomas, previously classified as nonfunctional, produce gonadotropins or their subunits.79 Indeed, as many as 40% to 50% of all macroadenomas may originate in gonadotropes.80 These tumors (Table 16-2) are generally recognized because of mass effects, such as visual impairment, headache, or the findings of sellar enlargement and pituitary mass on radiologic examination. The gonadotropins and their subunits that are produced only uncommonly lead to a clinical syndrome, partly explaining why these tumors were previously thought to be non-functional. Gonadotropin subunits have no known bioeffects, and the intact hormones are rarely produced in sufficient amount to cause a clinical syndrome. In fact, paradoxically, deficiencies of pituitary hormone secretion, especially of LH, are more commonly found, because the tumor mass compresses the normal pituitary, thereby impairing normal hormone production.

TABLE 16-2. Gonadotrope Adenomas of the Pituitary

The hormones produced by gonadotrope adenomas are, in decreasing order of frequency, FSH, LH, a subunit, and LH-b subunit. The elevations may be small, however, and could easily be mistaken for the elevations seen in mild primary hypogonadism. The administration of thyrotropin-releasing hormone can sometimes be useful because, in normal subjects, this hormone only rarely increases the secretion of gonadotropins or their subunits, whereas it may stimulate the secretion of these substances in patients with gonadotrope adenomas.81
Magnetic resonance imaging evaluation is important in assessing the existence and extent of a gonadotrope adenoma. In addition, magnetic resonance imaging is helpful in determining the position of the optic chiasm, the possibility of hemorrhage in the pituitary, and the differentiation of an adenoma from an aneurysm. Management also should include a thorough evaluation of pituitary function, including thyroid and glucocorticoid axes, as well as the exclusion of a prolactinoma, because these tumors may be treated medically.
Therapy for gonadotrope adenomas has been reviewed.82 Gonadotrope adenomas are principally treated with resection via the transsphenoidal approach. Indications for surgery include visual field and other neurologic deficits. Improvements are seen in as many as 90% of cases.83 Irradiation can be used in patients with residual tumor after initial surgery to prevent recurrence, in patients who are poor surgical candidates, or in those whose tumors are surgically inaccessible; however, the incidence of pituitary dysfunction afterward is significant.84 Medical therapies, such as administration of GnRH antagonists and somatostatin analogs, have been reported to decrease hormone levels; however, they do not cause regression of tumor size. Their role is probably limited to treating patients with aggressive tumors for whom other therapies have failed.

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