Gynecology_Novak

Gynecology_Novak. Patients with severe hirsutism, virilization, or recent and rapidly progressing signs of androgen excess require careful investigation for the presence of an androgen-secreting neoplasm. The two most common sources of androgen-secreting tumors are the adrenal glands and the ovaries. To assess the symptoms, serum and urine tests for androgens and their metabolites should be obtained along with modern abdominal imaging techniques such as CT, MRI, and ultrasound scans (194). In prepubertal girls, virilizing tumors may cause signs of heterosexual precocious puberty in addition to hirsutism, acne, and virilization. In patients suspected of harboring an adrenal or ovarian tumor because of rapidly progressing or severe hyperandrogenism, the bioavailable testosterone level (free testosterone level above 6.85 pg/mL; 23.6 pmol/L), followed by an11-desoxycortisol (above 7 ng/mL; 20.2 nmol/L), DHEAS (>3.6 μg/mL) and a 24-hour urinary cortisol (>45 μg per day) are the most sensitive and specific


Gynecology_Novak

Gynecology_Novak. above 6.85 pg/mL; 23.6 pmol/L), followed by an11-desoxycortisol (above 7 ng/mL; 20.2 nmol/L), DHEAS (>3.6 μg/mL) and a 24-hour urinary cortisol (>45 μg per day) are the most sensitive and specific for the detection of an androgen-secreting adrenocortical tumor (Table 31.3). A markedly elevated free testosterone level (2.5 times the upper normal range) is considered typical of an adrenal androgen-secreting tumor, while moderately elevated free testosterone levels are often ovarian in origin. A DHEAS level greater than 800 μg/dL is typical of an adrenal tumor. An adrenal tumor is unlikely when serum DHEAS and urinary 17-ketosteroid excretion measurements are in the normal basal range and the serum cortisol concentration is less than 3.3 μg/dL after dexamethasone administration (195). The results of other dynamic tests, especially testosterone suppression and stimulation, are unreliable (196).


Gynecology_Novak

Gynecology_Novak. A vaginal and abdominal ultrasonographic examination is the first step in the evaluation of findings suggesting ovarian neoplasm. Duplex Doppler scanning may increase the accuracy of tumor diagnosis and localization (197). CT scanning can reveal tumors larger than 10 mm (1 cm) in the adrenal gland but may not help to distinguish among different types of solid tumors or benign incidental nodules (198). In the ovaries, CT scanning cannot help differentiate hormonally active from functional tumors (197,198).


Gynecology_Novak

Gynecology_Novak. MRI is comparable, if not superior, to CT scanning in detecting ovarian neoplasms, but is neither more sensitive than high-quality ultrasound nor more useful in clinical decision making when ultrasound identifies a likely neoplasm. Nuclear medicine imaging of the abdomen and pelvis after injection with NP-59 ((131-iodine) 6-beta-iodomethyl-19-norcholesterol), preceded by adrenal and thyroid suppression, may facilitate tumor localization. In the rare circumstances when imaging fails to provide clear evidence for a neoplastic source of excess androgens, selective venous catheterization with measurement of site-specific androgen levels to identify an occult source of for androgen excess may be utilized (199). If all four vessels are catheterized transfemorally, selective venous catheterization allows direct localization of the tumor. Samples are obtained for hormonal analysis, with positive localization defined as a 5:1 testosterone gradient compared with lower vena cava values (200).


Gynecology_Novak

Gynecology_Novak. allows direct localization of the tumor. Samples are obtained for hormonal analysis, with positive localization defined as a 5:1 testosterone gradient compared with lower vena cava values (200). Under such circumstances specificity approaches 80%, but this rate should be weighed against the 5% rate of significant complications, such as adrenal hemorrhage and infarction, venous thrombosis, hematoma, and radiation exposure (201).


Gynecology_Novak

Gynecology_Novak. Ovarian neoplasms are the most frequent androgen-producing tumors. Granulosa cell tumors constitute 1% to 2% of all ovarian tumors and occur mostly in adult women (in postmenopausal more frequently than in premenopausal women) (see Chapter 37). Usually associated with estrogen production, they are the most common functioning tumors in children and can lead to isosexual precocious puberty (202). Patients can present with vaginal bleeding caused by endometrial hyperplasia or endometrial cancer resulting from prolonged exposure to tumor-derived estrogen (203). Total abdominal hysterectomy and bilateral salpingo-oophorectomy are the treatments of choice. If fertility is desired, a more conservative approach involving unilateral salpingo-oophorectomy with careful staging can be performed in women with stage IA (the cancer does not extend outside the involved ovary and a concomitant uterine cancer is excluded) (203). The malignant potential of these lesions is variable. The 10year survival


Gynecology_Novak

Gynecology_Novak. with stage IA (the cancer does not extend outside the involved ovary and a concomitant uterine cancer is excluded) (203). The malignant potential of these lesions is variable. The 10year survival rates vary from 60% to 90%, depending on the stage, tumor size, and histologic atypia (202).


Gynecology_Novak

Gynecology_Novak. Thecomas are rare and occur in older patients. In one study only 11% were androgenic, even in the presence of steroid-type cells (luteinized thecomas) (202). They are unilateral in more than 90% of the cases and rarely malignant. A unilateral oophorectomy is adequate treatment (204). Sclerosing stromal tumors are benign neoplasms that usually occur in patients younger than 30 years (202). A few cases with estrogenic or androgenic manifestations were reported.


Gynecology_Novak

Gynecology_Novak. Sertoli-Leydig cell tumors, previously classified as androblastoma or arrhenoblastoma, account for 11% of solid ovarian tumors. They contain various proportions of Sertoli cells, Leydig cells, and fibroblasts (202). Sertoli-Leydig cell tumors are the most common virilizing tumors in women of reproductive age; however, masculinization occurs in only one-third of patients. The tumor is bilateral in 1.5%. In 80% of cases, it is diagnosed at stage IA (202). Sertoli-Leydig cell tumors are frequently low-grade malignancies, and their prognosis is related to their degree of differentiation and stage of disease (205). Treatment with unilateral salpingo-oophorectomy is justified in patients with stage IA disease who desire fertility. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and adjuvant therapy are recommended for postmenopausal women who have advanced-stage disease.


Gynecology_Novak

Gynecology_Novak. Pure Sertoli cell tumors are usually unilateral. For a premenopausal woman with stage I disease, a unilateral salpingo-oophorectomy is the treatment of choice. Malignant tumors are rapidly fatal (206). Gynandroblastomas are benign tumors with well-differentiated ovarian and testicular elements. A unilateral oophorectomy or salpingo-oophorectomy is sufficient treatment. Sex cord tumors with annular tubules (SCTAT) are frequently associated with Peutz-Jeghers syndrome (gastrointestinal polyposis and mucocutaneous melanin pigmentation) (207). Their morphologic features range between those of the granulosa cell and Sertoli cell tumors. Whereas SCTAT with Peutz-Jeghers syndrome tend to be bilateral and benign, SCTAT without Peutz-Jeghers syndrome is almost always unilateral and malignant in one-fifth of cases (202).


Gynecology_Novak

Gynecology_Novak. Stromal hyperplasia is a nonneoplastic proliferation of ovarian stromal cells. Stromal hyperthecosis is defined as the presence of luteinized stromal cells at a distance from the follicles (211). Stromal hyperplasia, which is typically seen in patients between 60 and 80 years of age, may be associated with hyperandrogenism, endometrial carcinoma, obesity, hypertension, and glucose intolerance (211,212). Hyperthecosis is seen in a mild form in older patients. In patients of reproductive age, hyperthecosis may demonstrate severe clinical manifestations of virilization, obesity, and hypertension (213). Hyperinsulinemia and glucose intolerance may occur in up to 90% of patients with hyperthecosis and may play a role in the etiology of stromal luteinization and hyperandrogenism (72). Hyperthecosis is found in many patients with HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans).


Gynecology_Novak

Gynecology_Novak. In patients with hyperthecosis, levels of ovarian androgens, including testosterone, DHT, and androstenedione, are increased, usually in the male range. The predominant estrogen, as in PCOS, is estrone, which is derived from peripheral aromatization. The E1-to-E2 ratio is increased. Unlike in PCOS, gonadotropin levels are normal (214). Ovaries with stromal hyperthecosis have variable sonographic appearances (215). Wedge resection for the treatment of mild hyperthecosis was successful and resulted in resumption of ovulation and in a pregnancy (216). In cases of more severe hyperthecosis and high total testosterone levels, the ovulatory response to wedge resection is transient (214). In a study in which bilateral oophorectomy was used to control severe virilization, hypertension and glucose intolerance sometimes disappeared (217). When a GnRH agonist was used to treat patients with severe hyperthecosis, ovarian androgen production was dramatically suppressed (218).


Gynecology_Novak

Gynecology_Novak. Luteomas of pregnancy are frequently associated with maternal and fetal masculinization. This is not a true neoplasm but rather a reversible hyperplasia, which usually regresses postpartum. A review of the literature reveals a 30% incidence of maternal virilization and a 65% incidence of virilized female newborns in the presence of a pregnancy luteoma and maternal masculinization (219–221). Other tumors causing virilization in pregnancy include (in descending order of frequency) Krukenberg tumors, mucinous cystic tumors, Brenner tumors, serous cystadenomas, endodermal sinus tumors, and dermoid cysts (202). The most common virilizing adrenal neoplasms are adrenal carcinomas. Adrenocortical carcinomas are rare aggressive tumors that have a bimodal age incidence, with most cases presenting at ages 40 to 50 years (222). Virilization was reported in 20% to 30% of adults with functional adrenocortical carcinoma (223).


Gynecology_Novak

Gynecology_Novak. When these malignancies virilize, frequently they are associated with elevations in 11deoxycortisol, cortisol, and DHEAS. These tumors are commonly large and often detectable on abdominal examination. Adrenal tumors that secrete androgens exclusively, whether benign or malignant, are extraordinarily rare (194,224). Modern imaging techniques, such as CT, ultrasonography, MRI, or venous sampling, are extremely useful for distinguishing between an ovarian and an adrenal tumor as a cause of virilization (222).


Gynecology_Novak

Gynecology_Novak. Prolactin was first identified as a product of the anterior pituitary in 1933 (225). It is found in nearly every vertebrate species. Its presence in humans was long inferred by the association of the syndrome of amenorrhea and galactorrhea in the presence of pituitary macroadenomas, though it was not definitively identified as a human hormone until 1971. The specific activities of human prolactin (hPRL) were defined by the separation of its activity from growth hormone and subsequently by the development of radioimmunoassays (226–228). Although the initiation and maintenance of lactation is the primary function of prolactin, many studies document roles for prolactin activity both within and beyond the reproductive system.


Gynecology_Novak

Gynecology_Novak. Prolactin Secretion There are 199 amino acids within human prolactin, with a molecular weight (MW) of 23,000 D (Fig. 31.8). Although human growth hormone and placental lactogen have significant lactogenic activity, they have only a 16% and 13% amino acid sequence homology with prolactin, respectively. In the human genome, a single gene on chromosome 6 encodes prolactin. The prolactin gene (10 kb) has five exons and four introns, and its transcription is regulated in the pituitary by a proximal promotor region and in extrapituitary locations by a more upstream promotor (229).


Gynecology_Novak

Gynecology_Novak. In the basal state three forms are released: a monomer, a dimer, and a multimeric species, called little, big, and big-big prolactin, respectively (230–232). The two larger species can be degraded to the monomeric form by reducing disulfide bonds (233). The proportions of each of these prolactin species vary with physiologic, pathologic, and hormonal stimulation (233–236). The heterogeneity of secreted forms remains an active area of research. Studies indicate that little


Gynecology_Novak

Gynecology_Novak. Figure 31.8 Amino acid sequence of prolactin. Three cysteine disulfide bands are located within the molecule. (From Bondy PK. Rosenberg leukocyte esterase: metabolic control and disease, 8th ed. Philadelphia: WB Saunders, 1980, with permission.) prolactin (MW 23,000 D) constitutes more than 50% of all combined prolactin production and is most responsive to extrapituitary stimulation or suppression (233,235,236). Clinical assays for prolactin measure the little prolactin, and in all but extremely rare circumstances, these measures are sufficient to assess diseases of abnormal pituitary production of the hormone.


Gynecology_Novak

Gynecology_Novak. Prolactin, and its relatives growth hormone and placental lactogen, do not require glycosylation for most of their primary activities, as is the case for the gonadotropins and TSH. Glycosylated forms are secreted, and glycosylation does affect the bioactivity and immunoreactivity of little prolactin (237–240). It appears that the glycosylated form is the predominant species secreted, but the most potent biologic form appears to be the 23,000-D nonglycosylated form of prolactin (239). Prolactin has over 300 known biological activities. Prolactin’s most recognized activities include those associated with reproduction (lactation, luteal function, reproductive behavior) and homeostasis (immune responsivity, osomoregulation, and angiogenesis) (241). Despite these many activities, the only recognized disorder associated with deficiency of prolactin secretion is inability to lactate.


Gynecology_Novak

Gynecology_Novak. To some degree, the physical heterogeneity of prolactin may explain the biologic heterogeneity of this hormone, and although this complicates the physiologic evaluation of prolactin’s myriad effects, it is of little import to the diagnosis and management of hyperprolactinemic states.


Gynecology_Novak

Gynecology_Novak. In contrast to other anterior pituitary hormones, which are controlled by hypothalamic-releasing factors, prolactin secretion is primarily under inhibitory control mediated by dopamine. Multiple lines of evidence suggest that dopamine, which is secreted by the tuberoinfundibular dopaminergic neurons into the portal hypophyseal vessels, is the primary prolactininhibiting factor. Dopamine receptors were found on pituitary lactotrophs, and treatment with dopamine or dopamine agonists suppresses prolactin secretion (242–248). The dopamine antagonist metoclopramide abolishes the pulsatility of prolactin release and increases serum prolactin levels (244,245,249). Interference with dopamine transit from the hypothalamus to the pituitary by mass lesions, or blockade of the dopamine receptor as occurs with antipsychotic and other medications, increases serum prolactin levels. Thyrotropin-releasing hormone (TRH) causes prolactin release when present at supraphysiologic levels (as in primary


Gynecology_Novak

Gynecology_Novak. occurs with antipsychotic and other medications, increases serum prolactin levels. Thyrotropin-releasing hormone (TRH) causes prolactin release when present at supraphysiologic levels (as in primary hypothyroidism), but does not appear to play an important modulatory role in the normal physiologic regulation of prolactin secretion. γ -Aminobutyric acid (GABA) and other neurohormones and neurotransmitters may function as prolactin-inhibiting factors (250–253). Several hypothalamic polypeptides that modulate prolactin-releasing activity are listed in Table 31.9. It appears that dopamine and


Gynecology_Novak

Gynecology_Novak. Table 31.9 Chemical Factors Modulating Prolactin Release and Conditions that Result in Hyperprolactinemia Major surgery and disorders of chest wall (burns, herpes, chest percussion) Postpartum (nonnursing: days 1–7; nursing: with suckling) Table 31.9 Continued Metastatic tumors (especially of the lungs and breasts) Trauma to stalk Ectopic production (hypernephroma, bronchogenic sarcoma) Antidepressants (amoxapine, imipramine, amitriptyline) Dopamine antagonists (phenothiazines, thioxanthenes, butyrophenone, diphenylbutylpiperidine, dibenzoxazepine, dihydroindolone, procainamide, metoclopramide) TRH act as primary neurohormones, while others (i.e., neuropeptide Y, galanin, and enkephalin) act as modulators. It is likely that under differing physiologic conditions (i.e., pregnancy, lactation, stress, aging) a modulator may become a principal regulator of hormone secretion.


Gynecology_Novak

Gynecology_Novak. The prolactin receptor is a member of the class 1 cytokine receptor superfamily and is encoded by a gene on chromosome 5 (254). Transcriptional regulation of the prolactin receptor is accomplished through three tissue-specific promoter regions; promoter I for the gonads, promoter II for the liver, and promoter III, a generic promoter that includes the mammary gland (255). Hyperprolactinemia Physiologic disturbances, pharmacologic agents, or markedly compromised renal function may cause elevations in prolactin levels, and transient elevations occur with acute stress or painful stimuli. The most common cause of elevated prolactin levels is likely pharmacologic; most patients using antipsychotic medications and many other patients using agents with antidopaminergic properties will exhibit moderately elevated prolactin levels. Drug-related and physiologic conditions resulting in hyperprolactinemia do not always require direct intervention to normalize prolactin levels.


Gynecology_Novak

Gynecology_Novak. Evaluation Plasma levels of immunoreactive prolactin are 5 to 27 ng/mL throughout the normal menstrual cycle. Samples should not be drawn soon after the patient awakes or after procedures. Prolactin is secreted in a pulsatile fashion with a pulse frequency ranging from about 14 pulses per 24 hours in the late follicular phase to about 9 pulses per 24 hours in the late luteal phase. There also is a diurnal variation, with the lowest levels occurring in midmorning. Levels rise 1 hour after the onset of sleep and continue to rise until peak values are reached between 5 and 7 a.m. (256,257). The pulse amplitude of prolactin appears to increase from early to late follicular and luteal phases (258–260). Because of the variability of secretion and inherent limitations of radioimmunoassay, an elevated level should always be rechecked. This sample preferably is drawn midmorning and not after stress, previous venipuncture, breast stimulation, or physical examination, all of which transiently


Gynecology_Novak

Gynecology_Novak. level should always be rechecked. This sample preferably is drawn midmorning and not after stress, previous venipuncture, breast stimulation, or physical examination, all of which transiently increase prolactin levels.


Gynecology_Novak

Gynecology_Novak. When prolactin levels are found to be elevated, hypothyroidism and medications should first be ruled out as a cause. Prolactin and TSH determinations are basic evaluations in infertile women. Infertile men with hypogonadism should be tested. Likewise, prolactin levels should be measured in the evaluation of amenorrhea, galactorrhea, hirsutism with amenorrhea, anovulatory bleeding, and delayed puberty (Fig. 31.9).


Gynecology_Novak

Gynecology_Novak. Physical Signs Elevations in prolactin may cause amenorrhea, galactorrhea, both, or neither. Amenorrhea without galactorrhea is associated with hyperprolactinemia in approximately 15% of women (261–263). The cessation of normal ovulatory processes resulting from elevated prolactin levels is primarily caused by the suppressive effects of prolactin, via hypothalamic mediation, on GnRH pulsatile release (243,261,262,264–272). In addition to causing a hypogonadotropic state, prolactin elevations may secondarily impair the mechanisms of ovulation by causing a reduction in granulosa cell number and FSH binding, inhibition of granulosa cell 17βestradiol production by interfering with FSH action, and by causing inadequate luteinization and reduced luteal secretion of progesterone (273–278). Other etiologies for amenorrhea are detailed in Chapter 30.


Gynecology_Novak

Gynecology_Novak. Although isolated galactorrhea is considered indicative of hyperprolactinemia, prolactin levels are within the normal range in nearly 50% of such patients (279–281) (Fig. 31.9). In these cases, whether caused by a prior transient episode of hyperprolactinemia or other unknown factors, the sensitivity of the breast to the lactotrophic stimulus engendered by normal prolactin levels is sufficient to result in galactorrhea. This situation is very similar to that observed in nursing mothers in whom milk secretion, once established, continues and even increases despite progressive normalization of prolactin levels. Repeat testing is occasionally helpful in detecting hyperprolactinemia. Approximately one-third of women with galactorrhea have normal menses. Conversely, hyperprolactinemia commonly occurs in the absence of galactorrhea (66%), which may result from inadequate estrogenic or progestational priming of the breast.


Gynecology_Novak

Gynecology_Novak. In patients with both galactorrhea and amenorrhea (including the syndromes described and named by Forbes, Henneman, Griswold, and Albright in 1951, Argonz and del Castilla in 1953, and Chiari and Frommel in 1985), approximately two-thirds will have hyperprolactinemia; Hyperprolactinemia Review history, drug use, and physiologic etiologies


Gynecology_Novak

Gynecology_Novak. Hyperprolactinemia Review history, drug use, and physiologic etiologies Elevated TSH and hypothyroid by thyroid function tests Macroadenoma • Formal visual field test, • Neurosurgical consultation, • Discuss risks with pregnancy • Expectant management • Repeat MRI in 6–12 months Normal Repeat TSH Normal scan or hyperplasia Microadenoma Discuss risks with pregnancy • Repeat prolactin and TSH in 6 to 12 weeks • Document resolution • Amenorrhea • Progestin challenge Regular periods or Progestin challenge every 3 months Medical management Bromocriptine • Insure periods Resume or replace • Coned-down view may be appropriate in certain situations. • In cases of clear drug-induced hyperprolactinemia, a scan may not be required.


Gynecology_Novak

Gynecology_Novak. Micro or Macroadenoma • Prolactin remains elevated or recurs • CNS symptoms persist or recur Microadenoma • Decreased prolactin • Absent CNS signs or symptoms Macroadenoma • Prolactin levels and CNS symptoms return to normal No further scans required unless CNS signs or symptoms develop or prolactin level increases Initially scan at 6 months 1–4 years thereafter Neurosurgery Figure 31.9 Workup for hyperprolactinemia. TSH, thyroid-stimulating hormone; MRI, magnetic resonance imaging; CT, computed tomography; HRT, hormone replacement therapy; OCPs, oral contraceptive pills; CNS, central nervous system.


Gynecology_Novak

Gynecology_Novak. Figure 31.10 Prolactin levels in 235 patients with galactorrhea. Among patients with a tumor, open triangles denote associated acromegaly, and solid circles and solid triangles denote previous radiotherapy or surgical resection, respectively. (From Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977;296:589–600, with permission.) in that group, approximately one-third will have a pituitary adenoma (282). In anovulatory women, 3% to 10% of women diagnosed with polycystic ovary disease have coexistent and usually modest hyperprolactinemia (283,284) (Fig. 31.10).


Gynecology_Novak

Gynecology_Novak. Prolactin and TSH levels should be measured in all patients with delayed puberty. Pituitary abnormalities, including craniopharyngiomas and adenomas, should be considered in all cases of delayed puberty accompanied by low levels of gonadotropins, regardless of whether prolactin levels are elevated. When prolactin-secreting pituitary adenomas are present, the condition of multiple endocrine neoplasia type 1 (MEN-1) syndrome (gastrinomas, insulinoma, parathyroid hyperplasia, and pituitary neoplasia) should be considered, although symptoms of pituitary adenoma are rarely the presenting symptom. Patients who have a pituitary adenoma and a family history of multiple adenomas warrant special attention (285). Prolactinomas are noted in approximately 20% of patients with MEN-1. The MEN-1 gene is localized to chromosome 11q13 and appears to act as a constitutive tumor suppressor gene. An inactivating mutation results in development of the tumor. It is thought that prolactin-secreting pituitary


Gynecology_Novak

Gynecology_Novak. to chromosome 11q13 and appears to act as a constitutive tumor suppressor gene. An inactivating mutation results in development of the tumor. It is thought that prolactin-secreting pituitary adenomas that occur in patients with MEN-1 may be more aggressive than sporadic cases (286).


Gynecology_Novak

Gynecology_Novak. When an elevated prolactin level is documented and medications or hypothyroidism as the underlying cause is excluded, knowledge of neuroanatomy and imaging techniques and their interpretation is essential to further evaluation (see Chapter 7). Pituitary hyperprolactinemia is most often caused by a microadenoma or associated with normal imaging findings. These patients can be reassured that the probable course of their condition is benign. Macroadenomas or juxtasellar lesions are less common and require more complex evaluation and treatment, including surgery, radiation, or both. Levels of TSH should be measured in all patients with hyperprolactinemia (Fig. 31.9).


Gynecology_Novak

Gynecology_Novak. Imaging Techniques In patients with larger microadenomas and macroadenomas, prolactin levels usually are higher than 100 ng/mL. However, levels lower than 100 ng/mL may be associated with smaller microadenomas, macroadenomas that produce a “stalk section” effect, and suprasellar tumors that may be missed on a “coned-down” view of the sella turcica. Modest elevations of prolactin can be associated with microadenomas or macroadenomas, nonlactotroph pituitary tumors, and other central nervous system abnormalities; thus, imaging of the pituitary gland must be considered when otherwise unexplained and persistent prolactin elevation is present. In patients with a clearly identifiable drug-induced or physiologic hyperprolactinemia, imaging is not necessary unless accompanied by symptoms suggesting a mass lesion (headache, visual field deficits). MRI with gadolinium enhancement of the sella and pituitary gland appears to provide the best anatomic detail (287). The cumulative radiation dose


Gynecology_Novak

Gynecology_Novak. a mass lesion (headache, visual field deficits). MRI with gadolinium enhancement of the sella and pituitary gland appears to provide the best anatomic detail (287). The cumulative radiation dose from multiple CT scans may cause cataracts, and the “coned-down” views or tomograms of the sella are very insensitive and expose the patient to radiation. For patients with hyperprolactinemia who desire future fertility, MRI is indicated to differentiate a pituitary microadenoma from a macroadenoma and to identify other potential sellar-suprasellar masses. Although rare, when pregnancy-related complications of a pituitary adenoma occur, they occur more frequently in the presence of macroadenomas.


Gynecology_Novak

Gynecology_Novak. In over 90% of untreated women, microadenomas do not enlarge over a 4-to 6-year period. The argument that medical therapy will prevent a microadenoma from growing is false. Although prolactin levels correlate with tumor size, both elevations and reductions in prolactin levels may occur without any change in tumor size. If during follow-up a prolactin level rises significantly or central nervous system symptoms (headache, visual changes) are noted, repeat imaging may be indicated. Treatment is discussed below.


Gynecology_Novak

Gynecology_Novak. Hypothalamic Disorders Dopamine was the first of many substances whose production was demonstrated in the arcuate nucleus. Dopamine-releasing neurons innervate the external zone of the median eminence. When released into the hypophyseal portal system, dopamine inhibits prolactin release in the anterior pituitary. Lesions that disrupt dopamine release can result in hyperprolactinemia. Such lesions may arise from the suprasellar area, pituitary gland, and infundibular stalk, and from adjacent bone, brain, cranial nerves, dura, leptomeninges, nasopharynx, and vessels. Numerous pathologic entities and physiologic conditions in the hypothalamic–pituitary region can disrupt dopamine release and cause hyperprolactinemia.


Gynecology_Novak

Gynecology_Novak. In over one-third of women with hyperprolactinemia, a radiologic abnormality consistent with a microadenoma (<1 cm) is found. Release of pituitary stem cell growth inhibition via activation or loss-of-function mutations results in cell cycle dysregulation and is critical to the development of pituitary microadenomas and macroadenomas. Microadenomas are monoclonal in origin. Genetic mutations are thought to release stem cell growth inhibitors and result in autonomous anterior pituitary hormone production, secretion, and cell proliferation. Additional anatomic factors that may contribute to adenoma formation include reduced dopamine concentrations in the hypophyseal portal system and vascular isolation of the tumor or both. Recently, the heparin-binding secretory-transforming (HST) gene was noted in a variety of cancers and in prolactinomas (288). Patients with microadenomas can be reassured of a probable benign course, and many of these lesions exhibit gradual spontaneous regression


Gynecology_Novak

Gynecology_Novak. noted in a variety of cancers and in prolactinomas (288). Patients with microadenomas can be reassured of a probable benign course, and many of these lesions exhibit gradual spontaneous regression (289,290).


Gynecology_Novak

Gynecology_Novak. Both microadenomas and macroadenomas are monoclonal in origin. Pituitary prolactinomas and lactotrope adenomas are sparsely or densely granulated histologically. The sparsely granulated lactotrope adenomas have trabecular, papillary, or solid patterns. Calcification of these tumors may take the form of a psammoma body or a pituitary stone. Densely granulated lactotrope adenomas are strongly acidophilic tumors and appear to be more aggressive than sparsely granulated lactotrope adenomas. Unusual acidophil stem cell adenomas can be associated with hyperprolactinemia, with some clinical or biochemical evidence of growth hormone excess.


Gynecology_Novak

Gynecology_Novak. Microadenomas rarely progress to macroadenomas. Six large series of patients with microadenomas reveal that, with no treatment, the risk of progression for microadenoma to a macroadenoma is only 7% (291). Treatments include expectant, medical, or, rarely, surgical therapy. All affected women should be advised to notify their physicians of chronic headaches, visual disturbances (particularly tunnel vision consistent with bitemporal hemianopsia), and extraocular muscle palsies. Formal visual field testing is rarely helpful, unless imaging suggests compression of the optic nerves. Autopsy and radiographic series reveal that 14.4% to 22.5% of the US population harbor microadenomas, and approximately 25% to 40% stain positively for prolactin (292). Clinically significant pituitary tumors requiring some type of intervention affect only 14 per 100,000 individuals (292)


Gynecology_Novak

Gynecology_Novak. Expectant Management In women who do not desire fertility, expectant management can be used for both microadenomas and hyperprolactinemia without an adenoma while menstrual function remains intact. Hyperprolactinemia-induced estrogen deficiency, rather than prolactin itself, is the major factor in the development of osteopenia (293). Therefore, estrogen replacement with typical hormone replacement regimens or hormonal contraceptives is indicated for patients with amenorrhea or irregular menses. Patients with drug-induced hyperprolactinemia can be managed expectantly with attention to the risks of osteoporosis. In the absence of symptoms of pituitary enlargement, imaging may be repeated in 12 months, and if prolactin levels remain stable, less frequently thereafter, to assess further growth of the microadenoma.


Gynecology_Novak

Gynecology_Novak. Medical Treatment Ergot alkaloids are the mainstay of therapy. In 1985, bromocriptine was approved for use in the United States to treat hyperprolactinemia caused by a pituitary adenoma. These agents act as strong dopamine agonists, thus decreasing prolactin levels. Effects on prolactin levels occur within hours, and lesion size may decrease within 1 or 2 weeks. Bromocriptine decreases prolactin synthesis, DNA synthesis, cell multiplication, and overall size of prolactinomas. Bromocriptine treatment results in normal prolactin blood levels or return of ovulatory menses in 80% to 90% of patients.


Gynecology_Novak

Gynecology_Novak. Because ergot alkaloids, like bromocriptine, are excreted via the biliary tree, caution is required when using it in the presence of liver disease. The major adverse effects include nausea, headaches, hypotension, dizziness, fatigue and drowsiness, vomiting, headaches, nasal congestion, and constipation. Many patients tolerate bromocriptine when the dose is increased gradually, by 1.25 mg (one-half tablet) daily each week until prolactin levels are normal or a dose of 2.5 mg twice daily is reached. A proposed regimen is as follows: one-half tablet every evening (1.25 mg) for 1 week, one-half tablet morning and evening (1.25 mg) during the second week, one-half tablet in the morning (1.25 mg) and a full tablet every evening (2.5 mg) during the third week, and one tablet every morning and every evening during the fourth week and thereafter (2.5 mg twice a day). The lowest dose that maintains the prolactin level in the normal range is continued (1.25 mg twice daily often is sufficient to


Gynecology_Novak

Gynecology_Novak. evening during the fourth week and thereafter (2.5 mg twice a day). The lowest dose that maintains the prolactin level in the normal range is continued (1.25 mg twice daily often is sufficient to normalize prolactin levels in individuals with levels less than 100 ng/mL). Pharmacokinetic studies show peak serum levels occur 3 hours after an oral dose, with a nadir at 7 hours. Because little detectable bromocriptine is in the serum by 11 to 14 hours, twice-a-day administration is required. Prolactin levels can be checked soon (6 to 24 hours) after the last dose.


Gynecology_Novak

Gynecology_Novak. One rare, but notable, adverse effect of bromocriptine is a psychotic reaction. Symptoms include auditory hallucinations, delusional ideas, and changes in mood that quickly resolve after discontinuation of the drug (294). Many investigators report no difference in fibrosis, calcification, prolactin immunoreactivity, or the surgical success in patients pretreated with bromocriptine compared to those not receiving bromocriptine (291). An alternative to oral administration is the vaginal administration of bromocriptine tablets, which is well tolerated, and actually results in increased pharmacokinetic measures (295). Cabergoline, another ergot alkaloid, has a very long half-life and can be given orally twice per week. Its long duration of action is attributable to slow elimination by pituitary tumor tissue, high affinity binding to pituitary dopamine receptors, and extensive enterohepatic recirculation.


Gynecology_Novak

Gynecology_Novak. Cabergoline, which appears to be as effective as bromocriptine in lowering prolactin levels and in reducing tumor size, has substantially fewer adverse effects than bromocriptine. Very rarely, patients experience nausea and vomiting or dizziness with cabergoline; they may be treated with intravaginal cabergoline as with bromocriptine. A gradually increasing dosage helps avoid the side effects of nausea, vomiting, and dizziness. Cabergoline at 0.25 mg twice per week is usually adequate for hyperprolactinemia with values less than 100 ng/mL. If required to normalize prolactin levels, the dosage can be increase by 0.25 mg per dose on a weekly basis to a maximum of 1 mg twice weekly.


Gynecology_Novak

Gynecology_Novak. Recent studies reveal an increased risk of cardiac valve regurgitation in patients with Parkinson disease who were treated with high doses of cabergoline or pergolide but not with bromocriptine (296,297). Higher doses and a longer duration of therapy were associated with a higher risk of valvulopathy. It is postulated that 5HT2b-receptor stimulation leads to fibromyoblast proliferation (298). A recent cross-sectional study showed a higher rate of asymptomatic tricuspid regurgitation among cabergoline-treated patients compared to untreated patients with newly diagnosed prolactinomas as well as normal controls (299,300). The demonstrated relative safety of bromocriptine in reproductive-aged women and during more than 2,500 pregnancies suggest bromocriptine is the first choice for hyperprolactinemia and micro-and macroadenomas (301).


Gynecology_Novak

Gynecology_Novak. When bromocriptine or cabergoline cannot be used, other medications such as pergolide or metergoline may be used. In patients with a microadenoma who are receiving bromocriptine therapy, a repeat MRI scan may be performed 6 to 12 months after prolactin levels are normal, if indicated. Further MRI scans should be performed if new symptoms appear.


Gynecology_Novak

Gynecology_Novak. Discontinuation of bromocriptine therapy after 2 to 3 years may be attempted in a select group of patients who have maintained normoprolactinemia while on therapy (302,303). In a retrospective series of 131 patients treated with bromocriptine for a median of 47 months, normoprolactinemia was sustained in 21% at a median follow-up of 44 months after treatment discontinuation (303). Discontinuation of cabergoline therapy was successful in patients treated for 3 to 4 years who maintained normoprolactinemia (304). In cabergoline discontinuers who met stringent inclusion criteria, a recurrence rate of 64% was noted (305). A recent meta-analysis involving 743 patients noted sustained normoprolactinemia in only a minority of patients (21%) after discontinuation. Patients with 2 years or more of therapy before discontinuation and no demonstrable tumor visible on MRI had the highest chance of persistent normoprolactinemia (306). Recurrence rates are higher for macroadenomas (as compared to


Gynecology_Novak

Gynecology_Novak. of therapy before discontinuation and no demonstrable tumor visible on MRI had the highest chance of persistent normoprolactinemia (306). Recurrence rates are higher for macroadenomas (as compared to microadenomas or hyperprolactinemia without adenoma) after cessation of bromocriptine or cabergoline, warranting close follow-up with serum prolactin and MRI after cessation of therapy. In patients with macroadenomas, withdrawal of therapy should proceed with caution, as rapid tumor reexpansion may occur.


Gynecology_Novak

Gynecology_Novak. Macroadenomas are pituitary tumors that are larger than 1 cm in size. Bromocriptine is the best initial and potentially long-term treatment option, but transsphenoidal surgery may be required. High-dose cabergoline therapy was used in bromocriptine resistant or intolerant macroadenoma patients with success; however, cautions remain regarding the development of cardiac valve abnormalities (307). Evaluation for pituitary hormone deficiencies may be indicated. Symptoms of macroadenoma enlargement include severe headaches, visual field changes, and, rarely, diabetes insipidus and blindness. After prolactin has reached normal levels following ergot alkaloid treatment, a repeat MRI is indicated within 6 months to document shrinkage or stabilization of the size of the macroadenoma. This examination may be performed earlier if new symptoms develop or if there is no improvement in previously noted symptoms.


Gynecology_Novak

Gynecology_Novak. Medical Treatment Treatment with bromocriptine decreases prolactin levels and the size of macroadenomas; nearly one-half show a 50% reduction in size, and another one-fourth show a 33% reduction after 6 months of therapy. Because tumor regrowth occurs in more than 60% of cases after discontinuation of bromocriptine therapy, long-term therapy is usually required. After stabilization of tumor size is documented, the MRI scan is repeated 6 months later and, if stable, yearly for several years. This examination may be performed earlier if new symptoms develop or if there is no improvement in symptoms. Serum prolactin levels are measured every 6 months. Because tumors may enlarge despite normalized prolactin values, a reevaluation of symptoms at regular intervals (6 months) is prudent. Normalized prolactin levels or resumption of menses should not be taken as absolute proof of tumor response to treatment (306,308).


Gynecology_Novak

Gynecology_Novak. Surgical Intervention Tumors that are unresponsive to bromocriptine or that cause persistent visual field loss require surgical intervention. Some neurosurgeons have noted that a short (2-to 6-week) preoperative course of bromocriptine increases the efficacy of surgery in patients with larger adenomas (291). Unfortunately, despite surgical resection, recurrence of hyperprolactinemia and tumor growth is common. Complications of surgery include cerebral carotid artery injury, diabetes insipidus, meningitis, nasal septal perforation, partial or panhypopituitarism, spinal ﬂuid rhinorrhea, and third nerve palsy. Periodic MRI scanning after surgery is indicated, particularly in patients with recurrent hyperprolactinemia.


Gynecology_Novak

Gynecology_Novak. Occasionally, patients with hypothyroidism exhibit hyperprolactinemia with remarkable pituitary enlargement caused by thyrotroph hyperplasia. These patients respond to thyroid replacement therapy with reduction in pituitary enlargement and normalization of prolactin levels (309). Hyperprolactinemia occurs in 20% to 75% of women with chronic renal failure. Prolactin levels are not normalized through hemodialysis but are normalized after transplantation (310–312). Occasionally, women with hyperandrogenemia also have hyperprolactinemia. Elevated prolactin levels may alter adrenal function by enhancing the release of adrenal androgens such as DHEAS (313).


Gynecology_Novak

Gynecology_Novak. Numerous drugs interfere with dopamine secretion and can be responsible for hyperprolactinemia and its attendant symptoms (Table 31.9). If medication can be discontinued, resolution of hyperprolactinemia is uniformly prompt. If not, endocrine management should be directed at estrogen replacement and normalization of menses for those with disturbed or absent ovulation. Treatment with dopamine agonists may be utilized if ovulation is desired and the drug-inducing hyperprolactinemia cannot be discontinued. Use of Estrogen in Hyperprolactinemia


Gynecology_Novak

Gynecology_Novak. Use of Estrogen in Hyperprolactinemia In rodents, pituitary prolactin-secreting adenomas occur with high-dose estrogen administration (314). Elevated levels of estrogen, as found in pregnancy, are responsible for hypertrophy and hyperplasia of lactotrophic cells and account for the progressive increase in prolactin levels in normal pregnancy. The increase in prolactin during pregnancy is physiologic and reversible; adenomas are not fostered by the hyperestrogemia of pregnancy. Pregnancy may have a favorable inﬂuence on preexisting prolactinomas (315,316). Estrogen administration is not associated with clinical, biochemical, or radiologic evidence of growth of pituitary microadenomas or the progression of idiopathic hyperprolactinemia to an adenoma status (317–320). For these reasons, estrogen replacement or OC use is appropriate for hypoestrogenic patients with hyperprolactinemia secondary to microadenoma or hyperplasia.


Gynecology_Novak

Gynecology_Novak. Prolactin-secreting microadenomas rarely create complications during pregnancy. Monitoring of patients with serial gross visual field examinations and funduscopic examination is recommended. If persistent headaches, visual field deficits, or visual or funduscopic changes occur, MRI scanning is advisable. Because serum prolactin levels progressively rise throughout pregnancy, prolactin measurements are rarely of value. For those women who become pregnant while taking bromocriptine to treat a return of spontaneous ovulations, discontinuation of bromocriptine is recommended. This does not preclude subsequent use of bromocriptine during the pregnancy to treat symptoms (visual field defects, headaches) that arise from further enlargement of the microadenoma (301,321–323). Bromocriptine did not exhibit teratogenicity in animals, and observational data do not suggest harm to pregnancy or fetus in humans.


Gynecology_Novak

Gynecology_Novak. Bromocriptine did not exhibit teratogenicity in animals, and observational data do not suggest harm to pregnancy or fetus in humans. Pregnant women with previous transsphenoidal surgery for microadenomas or macroadenomas may be monitored with monthly Goldman perimetry visual field testing. Periodic MRI scanning may be necessary in women with symptoms or visual changes. Breastfeeding is not contraindicated in the presence of microadenomas or macroadenomas (301,321–323). The use of bromocriptine and presumably other dopaminergic agents that may cause blood pressure elevation during the postpartum period is contraindicated (324–328).


Gynecology_Novak

Gynecology_Novak. Thyroid disorders are 10 times more common in women than men. Approximately 1% of the female population of the United States will develop overt hypothyroidism (329). Even prior to the discovery of the long-acting thyroid stimulator (LATS) in women with Graves disease in 1956, numerous investigations demonstrated a link between these autoimmune thyroid disorders and reproductive physiology and pathology (330).


Gynecology_Novak

Gynecology_Novak. Thyroid Hormones Iodide is a critical component of the class of hormones known as thyronines, among which the most important are triiodothyronine (T3) and thyroxine (T4). Iodide obtained from dietary sources is actively transported into the thyroid follicular cell for the synthesis of these hormones. The sodium–iodide symporter (NIS) is a key molecule in thyroid function. It allows the accumulation of iodide from the circulation into the thyrocyte against an electrochemical gradient. The NIS requires energy that is supplied by Na-K ATPase, and iodine uptake is stimulated by TSH or thyrotropin. The enzyme thyroid peroxidase (TPO) then oxidizes iodide near the cell-colloid surface and incorporates it into tyrosyl residues within the thyroglobulin molecule, which results in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT). T3 and T4, formed by secondary coupling of MIT and DIT, are catalyzed by TPO. The membrane-bound, heme-containing oligomer, TPO, is localized in the


Gynecology_Novak

Gynecology_Novak. monoiodotyrosine (MIT) and diiodotyrosine (DIT). T3 and T4, formed by secondary coupling of MIT and DIT, are catalyzed by TPO. The membrane-bound, heme-containing oligomer, TPO, is localized in the rough endoplasmic reticulum, Golgi vesicles, lateral and apical vesicles, and on the follicular cell surface. Thyroglobulin, the major protein formed in the thyroid gland, has an iodine content of 0.1% to 1.1% by weight. About 33% of the iodine is present in thyroglobulin in the form of T3 and T4, and the remainder is present in MIT and DIT or found as unbound iodine. Thyroglobulin provides a storage capacity capable of maintaining a euthyroid state for nearly 2 months without the formation of new thyroid hormones. The thyroid antimicrosomal antibodies found in patients with autoimmune thyroid disease are directed against the TPO enzyme (331,332).


Gynecology_Novak

Gynecology_Novak. TSH regulates thyroidal iodine metabolism by activation of adenylate cyclase. This facilitates endocytosis as a component of iodide uptake, digestion of thyroglobulin-containing colloid, and the release of thyroid hormones T4,T3, and reverse T3.T4 is released from the thyroid at 40 to 100 times the concentration of T3. The concentration of reverse T3, which has no intrinsic thyroid activity, is 30% to 50% of T3, and 1% of T4 concentration. Of thyroid hormones released, 70% are bound by circulating thyroid-binding globulin (TBG). T4 is present in higher concentrations in the circulating storage pool and has a slower turnover rate than T3. Approximately 30% of T4 is converted to T3 in the periphery. Reverse T3 participates in regulation of the conversion of T4 to T3.T3 is the primary physiologically functional thyroid hormone at the cellular level. T3 binds the nuclear receptor with 10 times the affinity of T4. Thyroid hormone effects on cells include increased oxygen consumption, heat


Gynecology_Novak

Gynecology_Novak. functional thyroid hormone at the cellular level. T3 binds the nuclear receptor with 10 times the affinity of T4. Thyroid hormone effects on cells include increased oxygen consumption, heat production, and metabolism of fats, proteins, and carbohydrates. Systemically, thyroid hormone activity is responsible for the basal metabolic rate. It balances fuel efficiency with performance. Hyperthyroid states result in excessive fuel consumption with marginal performance.


Gynecology_Novak

Gynecology_Novak. Iodide Metabolism Normal function of the thyroid gland is dependent on iodine. The World Health Organization recommends 150 μg of iodine per day in women of reproductive age and 250 μg per day is recommended during pregnancy and nursing. Adequate iodination of household salt is defined as salt containing 15 to 40 mg of iodine per kilogram of salt (333). Optimal iodine intake to prevent disease lies within a relatively narrow range around the recommended daily consumption. Extreme iodine deficiency states are associated with cretinism, goiter, and hypothyroidism, while iodine sufficiency is associated with autoimmune thyroid disease and reduced remission rates in Graves disease (334).


Gynecology_Novak

Gynecology_Novak. Environmental factors associated with the occurrence of autoimmune thyroid diseases include pollutants (plasticizers, polychlorinated biphenyls) and exposure to infections such as yersinia enterocolitica, coxsackie B, Helicobacter pylori, and hepatitis C (335,336). For reasons not entirely known, women experience a 5-to 10-fold increased incidence of autoimmune thyroid disease (337). This difference is postulated to be the result of differences in sex steroid hormone levels, differences in environmental exposures, innate differences in female and male immune systems, and inherent chromosomal differences in the sexes (338,339). The immunoglobulins produced against the thyroid are polyclonal, and the multiple combinations of various antibodies consolidate to create the clinical spectrum of autoimmune thyroid diseases that may affect health and reproductive function.


Gynecology_Novak

Gynecology_Novak. Thyroid Function Measurements of free serum T4 and T3 are complicated by the low levels of free hormone in systemic circulation, with only 0.02% to 0.03% of T4 and 0.2% to 0.3% of T3 circulating in the unbound state (340). Of the T4 and T3 in circulation, approximately 70% to 75% is bound to TBG, 10% to 15% attached to prealbumin, 10% to 15% bound to albumin, and a minor fraction (<5%) is bound to lipoprotein (340,341). Total thyroid measurements are dependent on levels of TBG, which are variable and affected by many conditions such as pregnancy, oral contraceptive pill use, estrogen therapy, hepatitis, and genetic abnormalities of TBG. Thus, assays for the measurement of free T4 and T3 are more clinically relevant than measuring total thyroid hormone levels.


Gynecology_Novak

Gynecology_Novak. There are many different laboratory techniques to measure estimated free serum T4 and T3. These methods invariably measure a portion of free hormone that is dissociated from the in vivo protein bound moiety. This is of little clinical significance assuming the same proportions are measured for all assays and considered in the calibration of the assay (342). The T3 resin uptake test is an example of one laboratory method used to estimate free T4 in the serum. The T3 resin uptake (T3 RU) determines the fractional binding of radiolabeled T3, which is added to a serum sample in the presence of a resin that competes with TBG for T3 binding. The binding capacity of TBG in the sample is inversely proportional to the amount of labeled T3 bound to the artificial resin. Therefore, a low T3 resin uptake indicates high TBG T3 receptor site availability and implies high circulating TBG levels.


Gynecology_Novak

Gynecology_Novak. The free T4 index (FTI) is obtained by multiplying the serum T4 concentration by the T3 resin uptake percentage, yielding an indirect estimate of the levels of free T4: T3 RU% × T4 total = free T4 index. A high T3 RU percentage indicates reduced TBG receptor site availability and high free T4 index and thus hyperthyroidism, whereas a low T3 resin uptake percentage is a result of increased TBG receptor site binding and thus hypothyroidism. Equilibrium dialysis and ultrafiltration techniques may be used to determine the free T4 directly. Free T4 and T3 may also be determined by radioimmunoassay. Most available laboratory methods used for determining estimations of free T4 are able to correct for moderate variations in serum TBG but are prone to error in the setting of large variations of serum TBG, when endogenous T4 antibodies are present, and in the setting of inherent albumin abnormalities (340).


Gynecology_Novak

Gynecology_Novak. Because most disorders of hyperthyroidism and hypothyroidism are related to dysfunction of the thyroid gland and TSH levels are sensitive to excessive or deficient levels of circulating thyroid hormone, TSH levels are used to screen for these disorders. Current thyrotropin or TSH sandwich immunoassays are extremely sensitive and capable of differentiating low-normal from pathologic or iatrogenically subnormal values and elevations. TSH measurements provide the best way to screen for thyroid dysfunction and accurately predict thyroid hormone dysfunction in about 80% of cases (343). Reference values for TSH are traditionally based on the central 95% of values for healthy individuals, and some controversy exists regarding the upper limit of normal. Values in the upper limit of normal may predict future thyroid disease (342,344). In a longitudinal study, women with positive thyroid antibodies (TPOAbs or TgAbs), the prevalence of hypothyroidism at follow-up was 12.0% (3.0% to 21.0%; 95%


Gynecology_Novak

Gynecology_Novak. future thyroid disease (342,344). In a longitudinal study, women with positive thyroid antibodies (TPOAbs or TgAbs), the prevalence of hypothyroidism at follow-up was 12.0% (3.0% to 21.0%; 95% CI) when baseline TSH was 2.5 mU/L or less, 55.2% (37.1%–73.3%) for TSH between 2.5 and 4.0 mU/L, and 85.7% (74.1%–97.3%) for TSH above 4.0 mU/L (345). Physicians ordering thyrotropin


Gynecology_Novak

Gynecology_Novak. Table 31.10 Thyroid Autoantigens TSH, thyroid-stimulating hormone; ATP, adenosine triphosphate values should be aware of their limitations in the setting of acute illness, central hypothyroidism, the presence of heterophile antibodies, and TSH autoantibodies. In the setting of heterophile antibodies or TSH autoantibodies, TSH values will be falsely elevated (342). In cases of central hypothyroidism, decreased sialylation of TSH results in a longer half-life and a reduction in bioactivity (346,347). TSH levels may be elevated or normal when the patient remains clinically hypothyroid in states of central hypothyroidism, and successful treatment is often associated with low or undetectable TSH levels.


Gynecology_Novak

Gynecology_Novak. Many antigen–antibody reactions affecting the thyroid gland can be detected. Antibodies to TgAb, the TSH receptor (TSHRAb), TPOAb, the sodium iodine symporter (NISAb), and to thyroid hormone were identified and implicated in autoimmune thyroid disease states (348). A number of recognized thyroid autoantigens are listed in Table 31.10. Antibody production to thyroglobulin depends on a breach in normal immune surveillance (349,350). The incidence of thyroid autoantibodies in various autoimmune thyroid disorders is shown in Table 31.11. Antithyroglobulin antibodies are predominantly in the noncomplement fixing, polycolonal, immunoglobulin-G (IgG) class. Antithyroglobulin antibodies are found in 35% to 60% of patients with hypothyroid autoimmune thyroiditis, 12% to 30% of patients with Graves disease, and 3% of the general population (351–353). Antithyroglobulin antibodies are associated with acute thyroiditis, nontoxic goiter, and thyroid cancer (348).


Gynecology_Novak

Gynecology_Novak. Previously referred to as antimicrosomal antibodies, TPO antibodies are directed against thyroid peroxidase and are found in Hashimoto thyroiditis, Graves disease, and postpartum thyroiditis. The antibodies produced are characteristically cytotoxic, complement-fixing IgG antibodies. In patients with thyroid autoantibodies, 99% will have positive anti-TPO antibodies, whereas only 36% will have positive antithyroglobulin antibodies, making anti-TPO a more sensitive test for autoimmune thyroid disease (353). Anti-TPO antibodies are present in 80% to 99% of patients with hypothyroid autoimmune thyroiditis, 45% to 80% of patients with Graves disease, and 10% to 15% of the general population (352–354). These antibodies can cause artifact in the measurement of thyroid hormone levels. Antithyroid peroxidase antibodies are used clinically in Table 31.11 Prevalence of Thyroid Autoantibodies and Their Role in Immunopathology TSH, thyroid-stimulating hormone.


Gynecology_Novak

Gynecology_Novak. Table 31.11 Prevalence of Thyroid Autoantibodies and Their Role in Immunopathology TSH, thyroid-stimulating hormone. Table 31.12 Nomenclature of Anti-TSH Receptor Antibodies LATS Long-acting thyroid In vivo assay of stimulation Original description of serum stimulator of mouse thyroid molecule able to stimulate mouse thyroid; no longer used TSHRAb, TRAb TSHR antibodies Competitive and functional All antibodies recognizing the TSH assays described below receptor (includes TBII (competitive), and TSI, TBI and TNI (functional) based on assay method TBII TSHR-binding inhibitory Competitive binding assays Antibodies able to compete with immunoglobulin with TSH TSH for TSH receptor binding irrespective of biologic activity TSI (also TSAb) TSHR-stimulating Competitive and functional Antibodies able to block TSH immunoglobulins bioassays of TSH receptor receptor binding, induce cAMP activation production and nonclassical signaling cascades


Gynecology_Novak

Gynecology_Novak. TBI (also TSBAb, TSHBAb TSHR stimulation-blocking Functional bioassays of TSH Antibodies able to block TSH antibodies receptor activation receptor binding, induce cAMP production with +/– effects on nonclassical cascades TNI TSHR nonbinding Binding and functional assays No TSH binding, no effect on cAMP immunoglobulin levels and variable effects on nonclassical cascades TSH, thyroid-stimulating hormone. the diagnosis of Graves disease, the diagnosis of chronic autoimmune thyroiditis, in conjunction with TSH testing as a means to predict future hypothyroidism in subclinical hypothyroidism, and to assist in the diagnosis of autoimmune thyroiditis in euthyroid patients with goiter or nodules (348).


Gynecology_Novak

Gynecology_Novak. Another group of antibodies important in autoimmune thyroid disease bind the TSH receptor (TSHR). The TSHR belongs to the family of G-protein coupled receptors. TSHRAb are pathogenic and capable of activating (TSI) or blocking (TBI) TSH receptor functions. TBIs are detectable in two varieties: those that block TSH binding and those that block both pre-and postreceptor processes. Several investigators detected such blocking antibodies in patients with primary hypothyroidism and atrophic thyroid glands (355,356). The nomenclature and detection assay of TSH receptor antibodies are listed in Table 31.12. Anti-TSH receptor antibodies were reported in 6% to 60% of patients with hypothyroid autoimmune thyroiditis, 70% to 100% of patients with Graves disease, and 1% to 2% of the general population (357–361). Untreated Graves disease patients tested with third-generation immunometric assays are uniformly positive (362). TSHRAb are classified as binding inhibitory immunoglobulins by competitive


Gynecology_Novak

Gynecology_Novak. (357–361). Untreated Graves disease patients tested with third-generation immunometric assays are uniformly positive (362). TSHRAb are classified as binding inhibitory immunoglobulins by competitive binding assays (TBII); and in functional assays: stimulating (TSI)—according to their capacity to increase cyclic adenosine monophosphate (cAMP) production; blocking (TBI)—which possesses the capacity to reduce TSH effects; and, neutral (TNI)—with no effect on TSH binding or alteration of cAMP levels. A number of competitive and functional assays are available to determine the levels of each antibody type, which, in toto, correlate with severity of disease, extraglandular signs, risk of fetal effects, and chances for remission and recurrence. TSHRAb are used clinically to distinguish postpartum thyroiditis from Graves disease, to predict the risk of fetal and neonatal thyrotoxicosis in women with prior ablative treatment or current thionamide therapy in the setting of Graves disease, and


Gynecology_Novak

Gynecology_Novak. thyroiditis from Graves disease, to predict the risk of fetal and neonatal thyrotoxicosis in women with prior ablative treatment or current thionamide therapy in the setting of Graves disease, and in the diagnosis of euthyroid Graves ophthalmopathy (348). These assays will increasingly optimize individual patient testing and treatment (363).


Gynecology_Novak

Gynecology_Novak. Antibodies to the NIS are prevalent in a number of thyroid conditions. Anti-NISAbs were detected in 24% of patients with Hashimoto disease and 22% of patients with Graves disease (364). Anti-NISAbs are used experimentally (348).


Gynecology_Novak

Gynecology_Novak. The most common thyroid abnormalities in women, autoimmune thyroid disorders, represent the combined effects of the multiple thyroid autoantibodies (365). The various antigen–antibody reactions result in the wide clinical spectrum of these disorders. Transplacental transmission of some of these immunoglobulins may affect thyroid function in the fetus. The presence of autoimmune thyroid disorders, particularly Graves disease, is associated with other autoimmune conditions: Hashimoto thyroiditis, Addison disease, ovarian failure, rheumatoid arthritis, Sj¨ogren syndrome, diabetes mellitus (type 1), vitiligo, pernicious anemia, myasthenia gravis, and idiopathic thrombocytopenic purpura. Other factors that are associated with the development of autoimmune thyroid disorders include low birth weight, iodine excess and deficiency, selenium deficiency, parity, oral contraceptive pill use, reproductive age span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation


Gynecology_Novak

Gynecology_Novak. weight, iodine excess and deficiency, selenium deficiency, parity, oral contraceptive pill use, reproductive age span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation damage to the thyroid, and viral and bacterial infections (366).


Gynecology_Novak

Gynecology_Novak. Overt and subclinical hypothyroidism are defined as an elevated TSH with a low T4 and an elevated TSH and normal T4, respectively, using appropriate patient ranges (nonpregnant and pregnant). A number of professional organizations published various recommendations for thyroid function assessment via a TSH in women. Because of the long interval from development of disease to diagnosis, the nonspecific nature of symptoms, and the potential adverse neonatal and maternal outcomes associated with untreated hypothyroidism in pregnancy, the American Association of Clinical Endocrinologists (AACE) recommended screening women prior to conceiving or at the first prenatal appointment (367,368). The AACE also recommended screening for the presence of hypothyroidism in patients with type 1 diabetes mellitus (threefold increased risk of postpartum thyroid dysfunction and 33% prevalence overall), patients taking lithium therapy (35% prevalence), and consideration of testing in patients presenting


Gynecology_Novak

Gynecology_Novak. mellitus (threefold increased risk of postpartum thyroid dysfunction and 33% prevalence overall), patients taking lithium therapy (35% prevalence), and consideration of testing in patients presenting with infertility (>12% prevalence) or depression (10% to 12% prevalence), as these populations are at an increased risk of hypothyroidism (368). A screening TSH was recommended in women starting at the age of 50 because of the increased prevalence of hypothyroidism in this population (369). Thyroid function testing at 6-month intervals was recommended for patients taking amiodarone, as hyperthyroidism or hypothyroidism occurs in 14% to 18% of these patients (368). Any woman with a history of postpartum thyroiditis should be offered annual surveillance of thyroid function, as 50% of these patients will develop hypothyroidism within 7 years of diagnosis (370). Because there is a high prevalence of hypothyroidism in women with Turner and Down syndromes, an annual check of thyroid function is


Gynecology_Novak

Gynecology_Novak. will develop hypothyroidism within 7 years of diagnosis (370). Because there is a high prevalence of hypothyroidism in women with Turner and Down syndromes, an annual check of thyroid function is recommended for these patients (371,372).


Gynecology_Novak

Gynecology_Novak. Alternatively, the Endocrine Society’s clinical practice guidelines regarding the management of thyroid dysfunction during pregnancy and postpartum recommends targeted screening for the following individuals: history of thyroid disorder, family history of thyroid disease, goiter, thyroid autoantibodies, clinical signs or symptoms of thyroid disease, autoimmune disorders, infertility, head and/or neck radiation, and preterm delivery (373). The American Congress of Obstetricians and Gynecologists accepted these recommendations for TSH testing (374). Because of the (i) potentially significant neurologic affects on the fetus and other adverse pregnancy events; (ii) physiologic rise in TBG and the TSH-like activity of hCG in pregnancy, and (iii) potential for the targeted screening groups to have overt or subclinical hypothyroidism defined by the reference ranges for pregnancy (TSH <2.5, 3.1, and 3.5 μIU/mL for the first, second, and third trimesters, respectively), targeted maternal


Gynecology_Novak

Gynecology_Novak. to have overt or subclinical hypothyroidism defined by the reference ranges for pregnancy (TSH <2.5, 3.1, and 3.5 μIU/mL for the first, second, and third trimesters, respectively), targeted maternal testing for hypothyroidism is encouraged. The targeted screening protocol allows that 30% of subclinical hypothyroidism cases may be missed. According to these recommendations, preconceptionally diagnosed hypothyroid women (overt or subclinical) should have their T4 dosage adjusted such that the TSH value is less than 2.5 μIU/mL before pregnancy. The T4 dosage in women already on replacement will routinely require a dose escalation (30% to 50%) at 4 to 6 weeks gestation in order to maintain a TSH value less than 2.5 μIU/mL. Pregnant women with overt hypothyroidism should be normalized as rapidly as possible to maintain TSH at less than 2.5 and 3 μIU/mL in the first, second, and third trimesters, respectively. Euthyroid women with thyroid autoantibodies are at risk of hypothyroidism and


Gynecology_Novak

Gynecology_Novak. as possible to maintain TSH at less than 2.5 and 3 μIU/mL in the first, second, and third trimesters, respectively. Euthyroid women with thyroid autoantibodies are at risk of hypothyroidism and should have TSH screening in each trimester. After delivery, hypothyroid women need a reduction in T4 dosage used during pregnancy. Because subclinical hypothyroidism is associated with adverse outcomes for mother and the fetus, T4 replacement is recommended.


Gynecology_Novak

Gynecology_Novak. Figure 31.11 Types of autoimmune injury found in Hashimoto thyroiditis. A: Complement-mediated cytotoxicity, which can be abolished by inactivating the complement system. B: Antibody-dependent cell-mediated cytotoxicity (ADCC) function through killer T cells, monocytes, and natural killer cells that have immunoglobulin G fragment receptors. C: Stimulation of blockade of hormone receptors leading to hyperfunction or hypofunction or growth, depending on the types of immunoglobulins acting on the target cell. TBII, TSH-binding inhibitor immunoglobulin; TGI, thyroid growth–promoting immunoglobulin; TSAb, thyroid-stimulating antibodies; TSH, thyroid-stimulating hormone. (From Coulam CB, Faulk WP, McIntyre JA. Immunologic obstetrics. New York: Norton Medical Books, 1992:658, with permission.)


Gynecology_Novak

Gynecology_Novak. Hashimoto Thyroiditis Hashimoto thyroiditis, or chronic lymphocytic thyroiditis, was first described in 1912 by Dr. Hakaru Hashimoto. Hashimoto thyroiditis can manifest as hyperthyroidism, hypothyroidism, euthyroid goiter, or diffuse goiter. High levels of antimicrosomal and antithyroglobulin antibody are usually present, and TSHRAb may be present (353,375,376). Typically, glandular hypertrophy is found, but atrophic forms are also present. Three classic types of autoimmune injury are found in Hashimoto thyroiditis: (i) complement-mediated cytotoxicity, (ii) antibody-dependent cell-mediated cytotoxicity, and (iii) stimulation or blockade of hormone receptors, which results in hypo-or hyperfunction or growth (Fig. 31.11).


Gynecology_Novak

Gynecology_Novak. The histologic picture of Hashimoto thyroiditis includes cellular hyperplasia, disruption of follicular cells, and infiltration of the gland by lymphocytes, monocytes, and plasma cells. Occasionally, adjacent lymphadenopathy may be noted. Some epithelial cells are enlarged and demonstrate oxyphilic changes in the cytoplasm (Askanazy cells or H¨urthle cells, which are not specific to this disorder). The interstitial cells show fibrosis and lymphocytic infiltration. Graves disease and Hashimoto thyroiditis may cause very similar histologic findings manifested by a similar mechanism of injury. Clinical Characteristics and Diagnosis of Hashimoto Thyroiditis


Gynecology_Novak

Gynecology_Novak. Clinical Characteristics and Diagnosis of Hashimoto Thyroiditis Patients with Hashimoto thyroiditis may present with typical symptoms of hypothyroidism or may be relatively asymptomatic. Patients often present with a goiter, which can involve the parietal lobe. At later stages of the disease, hypothyroidism can be found without a goiter. Notable clinical manifestations associated with Hashimoto thyroiditis include fatigue, weight gain, hyperlipidemia, dry hair, dry skin, cold intolerance, depression, menstrual irregularities, bradycardia, and or memory impairment. Hashitoxicosis, the hyperthyroid manifestation of Table 31.13 Potential Causes of Hypothyroidism Congenital absence of thyroid gland Ingestion of antithyroid drugs Surgical removal of thyroid gland


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Gynecology_Novak. Table 31.13 Potential Causes of Hypothyroidism Congenital absence of thyroid gland Ingestion of antithyroid drugs Surgical removal of thyroid gland Hashimoto thyroiditis, may occur after a hypothyroid state and development into a euthyroid or hyperthyroid state and is thought to be the result of development of TSH-stimulating antibodies (TSI) associated with Graves disease (368). This variant is estimated to occur in 4% to 8% of patients with Hashimoto thyroiditis. In the setting of Hashitoxicosis, the patient requires frequent follow-up and the potential for adjustments in thyroid supplementation. These patients often become hypothyroid during the course of treatment.


Gynecology_Novak

Gynecology_Novak. In many cases, an elevated serum TSH is detected during routine screening. Elevated serum anti-TPO antibodies confirm the diagnosis, and free T4 and T3 document overt or subclinical hypothyroidsim. The sedimentation rate may be elevated, depending on the course of the disease at the time of recognition. Other causes of hypothyroidism should be considered, as listed in Table 31.13. Progression from subclinical to clinically overt hypothyroidism is reported to vary from 3% to 20%, with a higher risk noted in patients with goiter or thyroid antibodies (329,377). Treatment of subclinical hypothyroidism is somewhat controversial, but clinical studies suggested treatment of subclinical hypothyroidism is associated with a reduction in neurobehavioral abnormalities, a reduction in cardiovascular risk factors, and an improvement in lipid profile (378,379).


Gynecology_Novak

Gynecology_Novak. Thyroxine replacement is initiated in patients with clinically overt hypothyroidism or sub-clinical hypothyroidism with a goiter. Regression of gland size usually does not occur, but treatment often prevents further growth of the thyroid gland. Treatment is recommended for patients with subclinical hypothyroidism in the setting of a TSH greater than 10 mIU/L on repeat measurements, pregnant patients, a strong habit of tobacco use, signs or symptoms associated with thyroid failure, or patients with severe hyperlipidemia (380). All pregnant patients with an elevated TSH level should be treated with levothyroxine. Treatment does not slow progression of the disease. The initial dosage of levothyroxine may be as little as 12.5 μg per day up to a full replacement dose. The mean replacement dosage of levothyroxine is 1.6 μg/kg of body weight per day, although the dosage varies greatly between patients (368). Aluminum hydroxide (antacids), cholestyramine, iron, calcium, and sucralfate may


Gynecology_Novak

Gynecology_Novak. of levothyroxine is 1.6 μg/kg of body weight per day, although the dosage varies greatly between patients (368). Aluminum hydroxide (antacids), cholestyramine, iron, calcium, and sucralfate may interfere with absorption. Rifampin and sertraline hydrochloride may accelerate the metabolism of levothyroxine. The half-life of levothyroxine is nearly 7 days; therefore, nearly 6 weeks of treatment are necessary before the effects of a dosage change can be evaluated.


Gynecology_Novak

Gynecology_Novak. Hypothyroidism appears to be associated with decreased fertility resulting from disruption in ovulation, and thyroid autoimmune disease is associated with an increased risk of pregnancy loss with or without overt thyroid dysfunction (381). A meta-analysis of case-control and longitudinal studies performed since 1990 reveals a possible association between miscarriage and thyroid antibodies with an odds ratio of 2.73 (95% CI, 2.20–3.40). This association may be explained by a heightened autoimmune state affecting the fetal allograft or a slightly higher age of women with antibodies compared with those without antibodies (0.7 ± 1 year, p <.001) (382). Studies suggest that early subclinical hypothyroidism may be associated with menorrhagia (383).


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Gynecology_Novak. Severe primary hypothyroidism is associated with menstrual irregularities in 23% of women, with oligomenorrhea being the most common (382). Reproductive dysfunction in hypothyroidism may be caused by a decrease in the binding activity of sex hormone–binding globulin, resulting in increased estradiol and free testosterone and from hyperprolactinemia (382). The increase in prolactin levels is the result of enhanced sensitivity of the prolactinsecreting cells to TRH (with elevated TRH seen in primary hypothyroidism) and defective dopamine turnover resulting in hyperprolactinemia (384–387). Hyperprolactinemia-induced luteal phase defects are associated with less severe forms of hypothyroidism (388,389). Replacement therapy appears to reverse the hyperprolactinemia and correct ovulatory defects (390,391).


Gynecology_Novak

Gynecology_Novak. Combined thyroxine and triiodothyronine therapy is no more effective than thyroxine therapy alone, and patients with hypothyroidism should be treated with thyroxine alone (392). Treatment should target normalizing TSH values, and a daily dose of 0.012 mg up to a full replacement dose of levothyroxine (1.6 μg/kg of body weight per day) may be required with dosage dependent on the patient’s weight, age, cardiac status, and duration and severity of hypothyroidism (368).


Gynecology_Novak

Gynecology_Novak. Graves Disease Graves disease, characterized by exophthalmos, goiter, and hyperthyroidism, was first identified as an association of findings in 1835. A heritable specific defect in immunosurveillance by suppressor T lymphocytes is believed to result in the development of a helper T-cell population that reacts to multiple epitopes of the thyrotropin receptor. This activity induces a B-cell– mediated response, resulting in the clinical features of Graves disease (389). The TSHRAb bind to conformational epitopes in the extracellular domain of the thyrotropin receptor and are uniformly detected in patients with untreated Graves disease (390).


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Gynecology_Novak. Graves disease is a complex autoimmune disorder in which several genetic susceptibility loci and environmental factors are likely to play a role in the development of the disease. Human leukocyte antigen and polymorphisms in the cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene were established as susceptibility loci; however, the magnitude of their contributions seems to vary among patient populations and study groups. Additional loci are likely to be identified by a combination of genome-wide linkage analyses and allelic association analyses of candidate genes. The rate of concordance for Graves disease is only 20% in monozygotic twins and even lower in dizygotic twins, consistent with a multifactorial inheritance pattern highly inﬂuenced by environmental factors. Linkage analysis identified loci on chromosomes 14q31, 20q11.2, and Xq21 that are associated with susceptibility to Graves disease (393).


Gynecology_Novak

Gynecology_Novak. The classic triad in Graves disease consists of exophthalmos, goiter, and hyperthyroidism. The symptoms associated with Graves disease include frequent bowel movements, heat intolerance, irritability, nervousness, heart palpitations, impaired fertility, vision changes, sleep disturbances, tremor, weight loss, and lower extremity swelling. Physical findings may include lid lag, nontender thyroid enlargement (two to four times normal), onycholysis, dependent lower extremity edema, palmar erythema, proptosis, staring gaze, and thick skin. A cervical venous bruit and tachycardia may be noted. The tachycardia does not respond to increased vagal tone produced with a Valsalva maneuver. Severe cases may demonstrate acropachy, chemosis, clubbing, dermopathy, exophthalmos with ophthalmoplegia, follicular conjunctivitis, pretibial myxedema, and vision loss.


Gynecology_Novak

Gynecology_Novak. Approximately 40% of patients with new onset of Graves disease and many of those previously treated have elevated T3 and normal T4 levels. Abnormal T4 or T3 results are often caused by protein binding changes rather than altered thyroid function; therefore, assessment of free T4 and free T3 is indicated in conjunction with TSH. In Graves disease, the TSH levels are suppressed, and levels may remain undetectable for some time even after the initiation of treatment. Thyroid autoantibodies, including TSI, may be useful during pregnancy to more accurately predict fetal risk of thyrotoxicosis (368). Autonomously functioning, benign thyroid neoplasms that exhibit Table 31.14 Potential Causes of Hyperthyroidism


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Gynecology_Novak. Tumors secreting human chorionic gonadotropin (molar pregnancy, choriocarcinoma) a similar clinical picture include toxic adenomas and toxic multinodular goiter. A radioactive iodine uptake thyroid scan may help differentiate these two conditions from Graves disease. Rare conditions resulting in thyrotoxicosis include metastatic thyroid carcinoma causing thyrotoxicosis, amiodarone induced thyrotoxicosis, iodine induced thyrotoxicosis, postpartum thyroiditis, a TSH-secreting pituitary adenoma, an hCG-secreting choriocarcinoma, struma ovarii, and “de Quervan’s” or subacute thyroiditis (394). Factitious ingestion of thyroxine or desiccated thyroid should be considered in patients with eating disorders. Patients with thyrotoxicosis factitia demonstrate elevated T3 and T4, suppressed TSH, and a low serum thyroglobulin level, whereas other causes of thyroiditis and thyrotoxicosis demonstrate high levels of thyroglobulin. Potential causes of hyperthyroidism are listed in Table 31.14.


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Gynecology_Novak. Iodine-131 Ablation Treatment of women with hyperthyroidism of an autoimmune origin presents unique challenges to the physician who must consider the patient’s needs and her reproductive plans. Because the drugs used to treat this disorder have potentially harmful effects on the fetus, special attention must be given to the use of contraception and the potential for pregnancy.


Gynecology_Novak

Gynecology_Novak. A single dose of radioactive iodine-131 is an effective cure in about 80% of cases and is the definitive treatment in nonpregnant women. Any woman of childbearing age should be tested for pregnancy before undergoing diagnostic or therapeutic administration of iodine. Ablation of a second-trimester fetal thyroid gland and congenital hypothyroidism (cretinism) from treatment during the first trimester were reported (395). Nuclear medicine professionals provide expertise in the administration of the radioactive isotope, and because the effect of the radioactive iodine is not immediate, the endocrinologist continues to provide suppressive medical treatment for 6 to 12 weeks after administration of iodine while the patient remains hyperthyroid. As early as 2 to 3 months after treatment, patients may become hypothyroid and should be supplemented with thyroxine as indicated by serum levels of free thyroid hormone levels (368). TSH testing is not sensitive for predicting thyroid function


Gynecology_Novak

Gynecology_Novak. may become hypothyroid and should be supplemented with thyroxine as indicated by serum levels of free thyroid hormone levels (368). TSH testing is not sensitive for predicting thyroid function during this time as changes in TSH lag 2 weeks to several months behind thyroid function changes (368). Failure to respond to iodine 6 months after treatment may require a repeat treatment with radioactive iodine (394). Postablative hypothyroidism develops in 50% of patients within the first year after iodine therapy and in more than 2% of patients per year thereafter.


Gynecology_Novak

Gynecology_Novak. A higher rate of miscarriage was noted in women treated with iodine therapy in the year preceding therapy, but there is no reported increase in the rate of stillbirths, preterm birth, low birth weight, congenital malformation, or death after therapy (396). Many thyroidologists and nuclear medicine specialists are willing to allow pregnancy earlier than 1 year after therapy if patients receive replacement therapy with levothyroxine.


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Gynecology_Novak. Thyroid-Stimulating Receptor Antibody in Graves Disease The level of TSHRAb of the TBII class grossly parallels the degree of hyperthyroidism as assessed by the serum levels of thyroid hormones and total thyroid volume. Studies suggest that the combination of a small goiter volume (<40 mL) and a low TBII level (<30 U/L) results in a 45% chance of remission during the 5 years after completion of a 12-to 24-month course of antithyroid drug therapy (397). In contrast, the overall rate of relapse exceeded 70% in patients with a large goiter volume (>70 mL) and a higher TBII level (>30 U/L). The subgroup of patients with larger goiters and higher TBII levels had less than a 10% chance to remain in remission in the 5 years after treatment. Although it is not necessary for the diagnosis of Graves disease, except in some cases of multinodular goiter, a TSHRAb measurement may be a useful marker of disease severity. Used in combination with other clinical factors, it may contribute to initial


Gynecology_Novak

Gynecology_Novak. disease, except in some cases of multinodular goiter, a TSHRAb measurement may be a useful marker of disease severity. Used in combination with other clinical factors, it may contribute to initial decisions regarding treatment. See Table 31.12 for a review of the nomenclature and assay methods for TSHRAb.


Gynecology_Novak

Gynecology_Novak. Measurements of TSHRAb (TBII category) during treatment with antithyroid drugs are predictive of subsequent outcome. In one series, 73% of TBII-negative patients had remission compared with only 28% of TBII-positive patients who achieved remission after 12 months of antithyroid drug therapy (398). The duration of a course of antithyroid drug therapy may potentially be modified according to the TSHRAb status. In patients whose TSHRAb status became negative and antithyroid drug therapy was discontinued, the relapse rate was 41% compared with a rate of 92% for those patients who remained TSHRAb positive (399). Regardless of the rapidity of the disappearance of TSHRAb, it does seem that antithyroid drug therapy should be maintained for 9 to 12 months to minimize the risk of relapse. TSHRAb status appears to determine, in an inverse relationship, the reduction in thyroid volume after radioactive iodine therapy.


Gynecology_Novak

Gynecology_Novak. Third-generation TSHRAb assays have been developed, and their utility in evaluation and treatment monitoring is being evaluated. Many patients with Graves disease have or will develop antineutrophil cytoplasmic antibodies (ANCA) after treatment, but the significance of this finding is still under study. Smoking appears to be an independent risk factor for relapse after medical therapy and should be considered when planning treatment. Antithyroid Drugs Antithyroid drugs of the thioamide class include propylthiouracil (PTU) and methimazole. Low doses of either agent block the secondary coupling reactions that form T3 and T4 from MIT and DIT. At higher doses, they also block iodination of tyrosyl residues in thyroglobulin. Propylthiouracil additionally blocks the peripheral conversion of T4 to T3. Approximately one-third of patients treated by this approach alone go into remission and become euthyroid (397).


Gynecology_Novak

Gynecology_Novak. In 2009, the FDA published a warning on the use of propylthiouracil because of 32 reported cases of serious liver injury associated with its use (400,401). The average daily dose associated with liver failure was 300 mg, and liver failure was reported to occur anywhere from 6 days to 450 days after initiation of therapy (402). Traditionally PTU was the drug of choice to treat hyperthyroidism for the duration of pregnancy because it less readily crosses the placenta, and methimazole was associated with an increased risk of choanal atresia and aplasia cutis (403– 406). Because of the case reports of PTU-related liver failure and the increased risk of birth defects associated with methimazole use during embryogenesis, the FDA and the Endocrine Society recommend PTU never be used as first-line medical treatment of hyperthyroidism for nonpregnant patients. It is recommended that its use be limited to pregnant women during the first trimester; situations where surgery or radioactive iodine


Gynecology_Novak

Gynecology_Novak. medical treatment of hyperthyroidism for nonpregnant patients. It is recommended that its use be limited to pregnant women during the first trimester; situations where surgery or radioactive iodine treatment are contraindicated, and individuals who have developed a toxic reaction to methimazole (400,402). The FDA recommends monitoring patients closely for signs and symptoms of liver injury while taking PTU.If liver injury is suspected, PTU should be promptly discontinued (400). The American Thyroid Association recommends an initial dose of 100 to 600 mg per day in three divided doses with a goal to maintain T4 in the upper limit of normal using the lowest possible dose. Minor reactions such as pruritus affect 3% to 5% of patients treated with thionamide therapy, and antihistamines may eliminate symptoms and allow continued use. Agranulocytosis is a rare and potentially fatal complication of PTU and methimazole therapy, and developing in 0.2% of women treated, and it mandates immediate


Gynecology_Novak

Gynecology_Novak. symptoms and allow continued use. Agranulocytosis is a rare and potentially fatal complication of PTU and methimazole therapy, and developing in 0.2% of women treated, and it mandates immediate discontinuation of the drug (403). Agranulocytosis most commonly presents with fever and a sore throat followed by sepsis; the occurrence of fever, sore throat, or a viral-like syndrome should prompt an urgent evaluation.


Gynecology_Novak

Gynecology_Novak. Methimazole is the first-line drug for the treatment of hyperthyroidism, except in the first trimester of pregnancy, as it has been shown to be more effective than PTU at controlling severe hyperthyroidism and is associated with higher adherence rates and less toxicity (407). The American Thyroid Associated recommends initial daily doses of 10 to 40 mg per day in a single dose. Like treatment with PTU, the goal is to maintain a free T4 level in the upper limits of normal using the lowest possible dose. Free T4 levels show improvement 4 weeks after therapy, and TSH levels take 6 to 8 weeks to normalize (403). Methimazole use in pregnancy is associated with an 18-fold risk of fetal choanal atresia compared with the general population (95% CI, 3–121) (408). Congenital aplasia cutis was associated with maternal use of methimazole during pregnancy; however, it is not known at this time whether the risk (0.03%) is greater than that seen in the general population (409).


Gynecology_Novak

Gynecology_Novak. Studies suggest a potential role for an intrathyroid dexamethasone injection to prevent relapse (410). Other medical therapies include iodide and lithium, both of which reduce thyroid hormone release and inhibit the organification of iodine. Iodide leads to the secondary coupling of T3 and T4. Iodide inhibition of thyroid metabolism is only transient, and complete escape from inhibition occurs within 1 to 2 weeks of iodide therapy, making this useful only for acute management of severe thyrotoxicosis (394). Lithium may be used when thionamide therapy is contraindicated or in combination with PTU or methimazole (394). To avoid toxicity during treatment, serum lithium levels should be monitored. Lithium has been associated with fetal Ebstein anomaly, and iodide has been associated with congenital goiter; these medications should not be used in pregnant women and should be used with caution in women of reproductive age. Because of the complications related to medical therapy of


Gynecology_Novak

Gynecology_Novak. with congenital goiter; these medications should not be used in pregnant women and should be used with caution in women of reproductive age. Because of the complications related to medical therapy of hyperthyroidism, women desiring pregnancy should be counseled to strongly consider surgical treatment or radioactive iodine treatment prior to pregnancy (402).


Gynecology_Novak

Gynecology_Novak. Surgery Thyroidectomy was used for the treatment of Graves disease but is now rarely used unless there is a suspicion for coexisting thyroid malignancy (368). Potential candidates for surgical intervention include pregnant women refusing or not tolerating antithyroid medical therapy, pediatric patients presenting with Graves disease, or patients who refuse radioactive iodine therapy. Surgery is the most rapid and consistent method of achieving a euthyroid state in Graves disease and avoids the possible long-term risks of radioactive iodine. Surgical intervention may be considered in severe Graves ophthalmopathy. Patients should be rendered euthyroid before a thyroidectomy. The risks of surgery include postoperative hypoparathyroidism, recurrent laryngeal nerve paralysis, routine anesthetic and surgical risks, hypothyroidism, and failure to relieve thyrotoxicosis.


Gynecology_Novak

Gynecology_Novak. β-Blockers Propranolol occasionally is used with or without concurrent antithyroid medications before radioactive iodine or surgery to provide relief of symptoms. Larger and more frequent doses may be required because of a relative resistance to β-adrenergic antagonists in the setting of hyperthyroidism. Thyroid Storm Thyroid storm is an acute, life-threatening exacerbation of hyperthyroidism and should be treated as a medical emergency in an intensive care unit setting. Symptoms include tachycardia, tremor, diarrhea, vomiting, fever, dehydration, and altered mental status that may proceed to coma. Patients with poorly controlled hyperthyroidism are most susceptible. Beta-blocker agents, glucocorticoids, PTU (the action of which includes inhibition of T4-T3 conversion), and iodides are all key elements of therapy.


Gynecology_Novak

Gynecology_Novak. Because of the weak TSH-like activity of hCG, conditions with high levels of hCG, such as molar pregnancy, may be associated with biochemical and clinical hyperthyroidism. Symptoms regress with removal of the abnormal trophoblastic tissue and resolution of elevated levels of hCG. In a similar fashion, when hyperemesis gravidarum is associated with high levels of hCG, mild biochemical and clinical features of hyperthyroidism may be seen (411,412). Gestational trophoblastic disease is reviewed in Chapter 39.


Gynecology_Novak

Gynecology_Novak. Physicians should be aware of the changes in thyroid physiology during pregnancy. Pregnancy is associated with reversible changes in thyroid physiology that should be noted before diagnosing thyroid abnormalities (see Fig. 31.12 for pregnancy associated changes in TBG, total T4, hCG, TSH, and free T4) (403). Women with a history of hypothyroidism often require increased thyroxine replacement during pregnancy, and patients should have thyroid function tests performed at the first prenatal visit and during each trimester thereafter. Evidence suggests that optimal fetal and infant neurodevelopmental outcomes may require careful titration of replacement thyroxine that meets the frequently increased requirements of pregnancy (413,414).


Gynecology_Novak

Gynecology_Novak. Reproductive Effects of Hyperthyroidism to TBG. Relative serum concentration changes throughout pregnancy highlighting a fall in TSH associated with an increase in hCG early in pregnancy and a fall in free T4 as TBG levels rise during pregnancy. hCG, human chorionic gonadotropin; TSH, thyroid-stimulating hormone; TBG, thyroid-binding globulin, total T4, total thyroxine; free T4, free thyroxine. (Based on data from Brent GA. Maternal thyroid function: interpretation of thyroid function tests in pregnancy. Clin Obstet Gynecol 1997;40:3–15.) Postpartum, women should return to their prepregnancy dosage of levothyroxine and have a follow-up TSH checked 6 to 8 weeks postpartum.


Gynecology_Novak

Gynecology_Novak. Postpartum, women should return to their prepregnancy dosage of levothyroxine and have a follow-up TSH checked 6 to 8 weeks postpartum. High levels of TSAb (TSI) in women with Graves disease are associated with fetal-neonatal hyperthyroidism (415,416). Despite both the inhibition and elevation of gonadotropins seen in thyrotoxicosis, most women remain ovulatory and fertile (387,417). Severe thyrotoxicosis can result in weight loss, menstrual cycle irregularities, and amenorrhea. An increased risk of spontaneous abortion is noted in women with thyrotoxicosis. An increased incidence of congenital anomalies, particularly choanal atresia and possibly aplasia cutis, can occur in the offspring of women treated with methimazole (404,405,408).


Gynecology_Novak

Gynecology_Novak. Autoimmune hyperthyroid Graves disease may improve spontaneously, in which case antithyroid drug therapy may be reduced or stopped. TSHRAb production may persist for several years after radical radioactive iodine therapy or surgical treatment for hyperthyroid Graves disease. In this circumstance, there is a risk of exposing a fetus to TSHRAb. Fetal–neonatal hyperthyroidism is observed in 2% to 10% of pregnancies occurring in mothers with a current or previous diagnosis of Graves disease, secondary to the transplacental passage of maternal TSHRAb. This is a serious condition with a 16% neonatal mortality rate and a risk of intrauterine fetal death, stillbirth, and skeletal developmental abnormalities, such as craniosynostosis. Caution against overtreatment with antithyroid medication is warranted, as these medications may cross the placenta in sufficient quantities to induce fetal goiter. Guidelines for TSHRAb testing during pregnancy in women with previously treated Graves disease are


Gynecology_Novak

Gynecology_Novak. as these medications may cross the placenta in sufficient quantities to induce fetal goiter. Guidelines for TSHRAb testing during pregnancy in women with previously treated Graves disease are found in Table 31.15. Fetal goiters and the associated fetal hypo-or hyperthyroid status were diagnosed accurately in mothers with Graves disease using a combination of fetal ultrasonography of the thyroid with Doppler, fetal heart rate monitoring, bone maturation, and maternal TSHRAb and antithyroid drug status (418).