Endocrine Disturbances Affecting Reproduction

C H A P T E R 2 4 

Endocrine Disturbances Affecting Reproduction Alice Y. Chang Richard J. Auchus

The reproductive systems are vulnerable to disruption by internal and external forces including disease, malnutrition, and various forms of stress. The male and female axes are both susceptible to dysfunction from the same processes, although the female axis tends to be more sensitive. This chapter will review the influence of endocrine disorders of the pituitary, adrenal, and thyroid on reproduction. Each section will discuss the most important and relevant disorders of the specific gland and its effects on female reproduction first. Features specific for male reproduction will be discussed where relevant in each disease subsection. The reader is directed to Chapters 3, 17, and 20 for review of neuroendocrine disorders; Chapters 4, 16, and 17 for further discussion of congenital adrenal hyperplasia (CAH); Chapter 21 for a review of hyperandrogenism; and Chapter 27 for a review of endocrine disorders in pregnancy.

Pituitary Disorders ◆ Hypopituitarism from pituitary tumors and trauma tends to

follow an order of hormone loss: first growth hormone (GH), then luteinizing hormone (LH)/follicle-stimulating hormone (FSH), followed by thyroid-stimulating hormone (TSH), and finally adrenocorticotropic hormone (ACTH). ◆ Serum prolactin elevations from stalk compression rarely exceed 250 ng/mL. ◆ Indications for dopamine agonist therapy of microprolactinomas include galactorrhea, infertility, and estrogen deficiency; oral contraceptive pills are an alternative only for estrogen deficiency.

Overview As the “master gland,” the anterior pituitary gland controls the secretion of several essential hormones from other major endocrine glands, including the thyroid (releasing thyroxine and triiodothyronine), adrenal cortex (cortisol, dehydroepiandrosterone sulfate [DHEAS]), and gonads (predominantly 594

estradiol plus progesterone in females and testosterone in males). The anterior pituitary gland also produces GH and prolactin, which act directly on target organs. The actions of GH are largely exerted via the local or systemic production of insulin-like growth factor-1 (IGF1). The posterior pituitary regulates water metabolism via the production of vasopressin and induces milk letdown via the production of oxytocin. Disorders of the pituitary can be partial or complete, isolated to one hormone or multiple, and related to hormone deficiency or hormone excess. The axes controlled by the pituitary gland share the following basic principles: 1. Input from higher brain centers to the hypothalamus 2. Releasing and inhibitory factors influencing pituitary hormone secretion 3. Hypothalamic factor pulsatility, leading to pulsing of pituitary and target gland hormones 4. Feedback inhibition at both the hypothalamus and pituitary by active target gland hormones 5. Peripheral metabolism of target gland products 6. Influence of diurnal rhythm The relative importance of these regulatory components varies for each axis and is described below in more detail. These axes are shown schematically in Fig. 24.1. Of the pituitary axes, the thyroid axis is the simplest for several reasons. The primary product of the thyroid is thyroxine (T4), which is a precursor of the active hormone triiodothyronine (T3). Since T4 is heavily protein-bound, T4 has a long half-life (7 days), and T4 is slowly metabolized to T3. This scenario provides steady, well-dampened feedback, and the thyroid axis therefore shows high stability and low pulsatility. Hypothalamic thyrotropin-releasing hormone (TRH) pulses stimulate release of TSH; however, negative feedback by T3, primarily the pool generated via de-iodination of circulating T4 in the pituitary, tightly regulates TSH biosynthesis and primarily regulates the thyroid axis. Thus the thyroid axis is a model endocrine feedback system due to its stability and simplicity.



Abstract The reproductive axis, particularly in women, is vulnerable to disruption from environmental influences and illness. Endocrine disorders not involving the gonads strongly influence reproductive function. Diseases of the pituitary, adrenal, and thyroid can exert deleterious effects on ovulation, sex steroid production, implantation, and pregnancy outcomes. This chapter will review the presenting features, evaluation, and treatment of major endocrine disorders that affect reproduction, with emphasis on mechanisms that impair fertility.

Keywords Pituitary hyperprolactinemia adrenal Cushing syndrome Cushing disease hypothyroidism thyroid hyperthyroidism congenital adrenal hyperplasia

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FIGURE 24.1  The major factors regulating the anterior pituitary axes. (A) Thyroid axis; (B) adrenal axis; (C) growth-hormone (GH)-insulin-like growth factor-1 (IGF1) axis; (D) prolactin axis; (E) gonadal axis. The male gonadal axis is shown here; the corresponding female axis is discussed at length in Chapter 7. ACTH, Adrenocorticotropic hormone; AVP, (arginine) vasopressin; CRH, corticotropin-releasing hormone; DHEA-S, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; IL, interleukin; LH, luteinizing hormone; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.

In contrast, the adrenal axis is characterized by a strong diurnal rhythm, with the shorter half-life of cortisol (1 hour) leading to greater pulsatility. The adrenal axis is also more sensitive to factors beyond hypothalamic corticotropinreleasing hormone (CRH) and negative feedback by cortisol. Both vasopressin and various cytokines increase production of corticotropin (ACTH) in response to stress or illness. As a consequence, this intricate feedback system provides a more responsive axis to physiologic changes and needs. This level of sophistication, however, complicates clinical testing. The GH (somatotropin) axis is primarily a two-component axis regulated by the hypothalamus. Growth hormone– releasing hormone (GHRH) serves as the major positive stimulus and somatostatin (SS) as the major negative stimulus. GH stimulates the production of IGF1 in the liver and locally in other tissues. Circulating IGF1 derives from the liver and exerts some negative feedback on the axis, but this influence is small relative to SS. Numerous hormonal and metabolic factors, however, also alter GH secretion by modulating the release of GHRH and SS. While the two

hypothalamic hormones regulate GH pulsatility throughout the day, the greatest GH pulses are produced in slow-wave sleep. Significant physical stressors, including hypoglycemia, also increase GH secretion. Prolactin is the only anterior pituitary hormone that is primarily under negative control, mediated by dopamine. For this reason, prolactin rises whenever blood flow to the pituitary from the hypothalamus is impaired. Therefore, hyperprolactinemia can result from a large pituitary tumor, which does not itself secrete prolactin, by blocking blood flow from the stalk. Prolactin is also increased by stress, nipple stimulation, and TRH, so prolactin rises transiently for several reasons and persistently for several others (Table 24.1). Prolactin acts on the breast to enable lactation, but there is no known hormonal product from the breast that exerts negative feedback on prolactin secretion. Estrogens also stimulate lactotrope growth. The gonadotropins LH and FSH and their regulation by gonadotropin-releasing hormone (GnRH) are discussed in detail for the male and female in other chapters. Here we

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Table 24.1  Causes of Hyperprolactinemia Cause

Characteristic Features(s)

Prolactinoma Acromegaly

Mass effects if macroadenoma Headaches, heavy perspiration, acral changes Peripheral vision loss, anterior pituitary defects Anterior pituitary defects, can have diabetes insipidus Other specific side effects of drug Positive human chorionic gonadotropin, amenorrhea Comorbidities of renal failure Variable prolactin Including phlebotomy See Table 24.4

Macroadenoma (not prolactin secreting) Other infiltrative or hypothalamic diseases Drugs Pregnancy Renal failure Chest wall stimulation Stress Primary hypothyroidism

simply emphasize that pulsatile GnRH secretion every 90 to 120 minutes is critical to LH and FSH production. While this principle is true for both males and females, the influence on fertility and symptoms differs in other respects. The reproductive axis is particularly sensitive to disorders and disruptions of the pituitary-hypothalamic axes as discussed in further detail later. Loss of pituitary function is most commonly caused by drugs, exogenous hormones, or tumors. Tumors affect pituitary function by overproduction of hormones, such as prolactin impairing gonadotropin secretion and hypercortisolism lowering TSH and gonadotropins, or by mass effect. Any pituitary tumor greater than 1 cm in maximal diameter is defined as a macroadenoma. The acquisition of pituitary hormone deficiencies due to tumors tends to follow the order GH first, then LH + FSH, then TSH, and finally ACTH.1 Consequently, the reproductive axis is fairly vulnerable to disruption by macroadenomas of any cell type. Decompression by transsphenoidal surgery can restore pituitary function, particularly for the ACTH and TSH axes,2,3 but iatrogenic hypopituitarism is a common risk of surgery. Radiotherapy tends to cause hypopituitarism over a period of 2 to 15 years and for this reason should be used judiciously in women of reproductive age.4 In the following discussion, both the nature of the pituitary disorder and its treatment are addressed as they affect strategies for restoring reproductive function.

Pituitary Disorders That Affect Reproduction Prolactinoma and Hyperprolactinemia The combination of amenorrhea and galactorrhea in a young woman is a classic presentation of prolactinoma; however, these two symptoms may occur individually or not at all.5 Hyperprolactinemia has many potential etiologies (see Table 24.1) (see Chapter 3). The mechanisms of reproductive dysfunction in hyperprolactinemia vary somewhat with etiology, but prolactin disrupts the pulses of GnRH and also directly reduces the production of LH and FSH.6-8 The diagnosis of hyperprolactinemia is established by measuring a serum prolactin at any time of day without dynamic testing, although the stress of phlebotomy can cause slight elevations.9 Falsely elevated prolactin measurements can be caused by the presence of macroprolactin, also known

as big-big prolactin,10 which is a complex of prolactin and IgG detected variably in different immunoassays but lacking normal biological activity.11,12 If the prolactin is clearly elevated and causes other than pituitary tumors are excluded, a dedicated magnetic resonance image (MRI) of the sella with gadolinium contrast agent should be performed. Microprolactinomas (tumors <1 cm in greatest diameter) are found in about 1% of women ages 20 to 40 years old.13 The degree of prolactin elevation is roughly proportional to the size of the tumor.14 A tumor not secreting prolactin might cause hyperprolactinemia via stalk compression and impaired dopamine delivery,15 but the prolactin rarely if ever rises above 250 ng/mL.16 For example, a patient with a 3-cm pituitary mass and a prolactin of 150 ng/mL probably does not have a prolactinoma. In cases of large pituitary tumors with mild prolactin elevations, however, the prolactin measurement should be repeated with dilutions to identify the “high-dose hook effect,” which artifactually lowers the assayed value.17 GH is a full prolactogen in humans; consequently, galactorrhea with mildly elevated prolactin and a pituitary tumor could be secondary to a somatotropinoma rather than prolactinoma.18 On T1-weighted MRI with gadolinium contrast, microprolactinomas tend to be hypointense (hypoenhancing) relative to the normally bright pituitary and usually do not distort the architecture of the gland (Fig. 24.2). Although the larger macroprolactinomas tend to enhance with gadolinium, the pattern is quite variable, and macroprolactinomas tend to distort the architecture of the gland (Fig. 24.3) with the inferior portion of the pituitary stalk often deviating away from the tumor. Prolactinomas are generally very responsive to medical therapy with dopamine agonists (bromocriptine and cabergoline).19 Even for large and invasive macroprolactinomas with visual changes, tumor shrinkage by dopamine agonists can be immediate and effective (see Fig. 24.3). Treatment options are selected based on symptoms, tumor size, and patient goals.20 Indications for treatment include infertility, amenorrhea, galactorrhea (particularly if spontaneous and bothersome), hypopituitarism, and mass effect. A woman with a 5-mm microprolactinoma, serum prolactin of 60 ng/ mL, regular menses, and only trace expressible galactorrhea does not require treatment, because these tumors rarely grow.21,22 In contrast, the same woman with infertility would be treated if she desires pregnancy. Cyclic estrogen and progestin for endometrial and bone protection or symptoms of estrogen deficiency is an option for patients with microprolactinomas and irregular menses but without galactorrhea and who do not desire pregnancy, with low risk of tumor growth.23-25 Bromocriptine is administered in two to three divided doses with a total of 2.5 to 40 mg/day. The main side effects of bromocriptine are nausea, lightheadedness, and nasal stuffiness. The dose is slowly advanced every 4 to 10 days as tolerated until the serum prolactin is normalized and the symptoms are relieved. Cabergoline, administered at 0.25 to 2 mg once or twice weekly,26 is much more potent and better tolerated than bromocriptine. Bromocriptine is generally preferred if pregnancy is desired, stopping the medication upon confirming conception.20 Cabergoline use early in pregnancy was not found to increase the risk for miscarriage or fetal malformations and is generally considered safe also.27 Visual fields and serum prolactin should be monitored

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**

A

* * B

FIGURE 24.2  MRI of pituitary microadenoma. (A) Normal pituitary. In this T1-weighted coronal image after gadolinium contrast, the pituitary gland is seen in the area of high signal below the pituitary stalk (chevron arrowhead). The carotid arteries are indicated by thin arrows, and the optic nerves are labeled with asterisks (*). (B) Pituitary microadenoma. The thick arrow shows the tumor as a hypointensity within the high-signal pituitary gland.

*

A

B

FIGURE 24.3  Macroprolactinoma and response to cabergoline. (A) T1-weighted coronal image after gadolinium contrast at diagnosis with a serum prolactin of 350 ng/mL. The tumor is pressing against the optic nerve on the right (reader’s left, *). (B) After 3 months of treatment with cabergoline at 0.5 mg twice weekly, the serum prolactin had fallen to 10 ng/mL. The stalk is now visible (arrows), and the tumor no longer abuts the optic nerve (black rim separating the tumor from the optic nerve).

throughout pregnancy and during lactation, more closely for macroprolactinomas. MRI without contrast is performed if tumor growth is suspected, and cabergoline is restarted to prevent vision compromise and/or hypopituitarism during pregnancy. In some cases, particularly those in which the tumor has become no longer visible on MRI scan, cabergoline can be discontinued after 2 to 5 years without recurrence of hyperprolactinemia.28 Chronic treatment with high doses of cabergoline for Parkinson disease has been rarely associated with cardiac valve disease29,30 due to the serotonin receptor agonism by cabergoline but not bromocriptine. An approximately threefold increased prevalence of asymptomatic mild31 or moderate32 tricuspid regurgitation was detected echocardiographically in cabergoline-treated prolactinoma patients compared to controls, particularly at higher cumulative doses. Consequently, periodic cardiac exam is necessary in patients treated with cabergoline, and echocardiography is indicated if a murmur is appreciated or if high doses are required. Surgery and radiotherapy are reserved primarily for rare tumors unresponsive to dopamine agonists and for patients intolerant to these drugs.20 Surgery is most effective for microadenomas, with success rates approaching 90% for

microadenomas but only about 60% for macroprolactinomas.33,34 An immediate postoperative prolactin of less than 2 ng/mL is reliable evidence of cure. Radiotherapy takes at least a year to lower the prolactin significantly and to stop tumor growth. Resumption of ovulatory cycles and spontaneous conception has been reported after Gamma Knife radiosurgery.35 Occasionally, patients present with normoprolactinemic galactorrhea and regular menses. If the galactorrhea is bothersome, treatment with bromocriptine or cabergoline to lower the prolactin to less than 2 ng/mL is effective in stopping the galactorrhea.36 The duration of therapy required is roughly proportional to the duration of time that the galactorrhea has been present. Patients should be counseled to wear a tight bra or breast binder and to avoid both nipple stimulation and testing themselves for expressible milk production during the course of therapy. In men, the majority of patients with prolactinoma come to medical attention with macroprolactinomas and markedly elevated prolactin values.37 Men present with symptoms attributable either to mass effect, such as vision loss and diplopia, or to hypogonadism, including fatigue, loss of libido, and erectile dysfunction.38 Galactorrhea is rare but seen if

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Combined modality therapy is the norm for the typical invasive somatotropinoma (Fig. 24.4). Large tumors often require both transsphenoidal surgery and sometimes craniotomy to debulk the tumor sufficiently for drug or radiotherapy,47 whereas for microadenomas, cure rates are high and hypopituitarism infrequent for experienced pituitary neurosurgeons.48 Pure somatotropinomas occasionally respond to high doses of dopamine agonists with reduced GH secretion and/or tumor shrinkage.49 Many somatotropinomas express SS receptors, primarily type 2 (sst2), and remain responsive to SS agonists such as octreotide or lanreotide, given as monthly long-acting intramuscular or deep subcutaneous injections of 10 to 40 mg or 60 to 120 mg, respectively. Although earlier reports suggested GH and IGF1 normalization in 70% of patients, more recent studies indicate that less than 40% of patients normalize on SS agonist therapy.50,51 Some tumor shrinkage occurs in over half of somatotropinomas treated with SS analogues, but the degree of regression is not as dramatic as for prolactinomas treated with dopamine agonists. Pegvisomant, a GH receptor antagonist that is modified with polyethylene glycol, normalizes IGF1 in up to 95% of patients during the initial trials,52 but long-term studies indicate that the success rate is 60% to 65%.53 The drug is given by subcutaneous injection of 40 mg as loading dose, followed by 10 to 30 mg/day, and it is generally well tolerated except for transaminase elevation in rare cases. Pasireotide, which binds to sst5 with higher affinity than octreotide, was found to achieve biochemical control in more patients than octreotide or lanreotide but causes more hyperglycemia.54,55 GH normally rises in pregnancy due to the secretion of placental GH, which is the product of a separate gene from pituitary GH. Consequently, medical treatment is normally withheld during pregnancy.

gynecomastia is present and hyperprolactinemia is severe. Sperm count is usually reduced only after many years of hyperprolactinemia. Indications for treatment include mass effects and hypopituitarism. The hypogonadism associated with prolactinomas in men often responds well to dopamine agonist therapy, unless the duration of hypogonadism is prolonged. The erectile dysfunction of hyperprolactinemia does not always improve with testosterone replacement unless the prolactin is normalized.38,39 Sperm count is not immediately restored by dopamine agonist therapy and may not return to normal after many months of therapy.

Acromegaly Acromegaly results from overproduction of GH and IGF1 accompanied by acral bone and soft tissue growth. Because symptoms are subtle and gradual in onset, the diagnosis may be delayed for several years. Additional symptoms and complications include fatigue, sleep apnea, hyperhidrosis, headache, and carpal tunnel syndrome. The majority of patients with acromegaly have a GH-secreting pituitary tumor (somatotropinomas), less than 10% have GHRH-producing tumors, usually pancreatic neuroendocrine tumors. Menstrual abnormalities are observed when tumor mass effect impairs delivery of hypothalamic releasing factors to the anterior pituitary or when hyperprolactinemia occurs. The direct action of GH can cause galactorrhea; however, tumors that cosecrete GH and prolactin also exist, which complicates the evaluation.40 Prolactin cosecretion does not predict an improved response to dopamine agonist therapy.41 A serum IGF1, corrected for gender and age or Tanner stage, is the best screening test for acromegaly. An elevated IGF1 plus acral changes in a patient with a pituitary tumor are usually sufficient to make the diagnosis. Formal GH suppression testing with 100 grams of glucose (normal GH <0.1 ng/mL in males or <1 ng/mL in females42) is used mainly to gauge response to therapy when IGF1 is equivocal, using a value of <0.4 or <1 ng/mL as remission.43 Gigantism occurs when the tumor forms prior to closure of the epiphyses.44,45 Genetic causes of acromegaly and gigantism include multiple endocrine neoplasia type 1 (MEN1, MEN1 gene), Carney complex (PRKA1A gene), and familial isolated pituitary adenoma (FIPA, AIP gene).46

Cushing Disease Hypercortisolism from ACTH-producing pituitary tumors causes infertility both from the effects of glucocorticoids on the hypothalamic-pituitary-gonadal axis and from mass effect if it is caused by a macroadenoma. This topic will be covered in the adrenal section below, and the principles of hypopituitarism from macroadenomas are the same as discussed earlier.

* * A

B

FIGURE 24.4  Magnetic resonance image of invasive somatotropinomas. The tumor in (A) invades the carotid sinus on the left (reader’s right, chevron arrowheads) and obliterates the optic nerve on that side. The tumor on (B) has heterogeneous intensity from internal hemorrhage, and this tumor invades the carotid sinus on the right (reader’s left, chevron arrowheads). The stalk (arrow) is visible on the left (reader’s right), but the normal pituitary is not discernable. The optic nerves (*) are not compromised, and diploic space (between arrowheads) is expanded.



Other Macroadenomas Many pituitary adenomas are nonfunctional, meaning that they do not produce significant amounts of biologically active hormones. Most of these tumors, however, derive from the glycoprotein hormone cell lineage and express mRNA for the common alpha subunit and/or the beta subunits of LH, FSH, or TSH,56 but the glycoprotein products are biologically inactive due to improper glycosylation, dimerization, and assembly.57 In general, these tumors present with symptoms due to mass effect (vision loss, headache) and/or hypopituitarism. Unlike prolactinomas, these tumors tend to be resistant to medical therapy. Indications for surgery include vision compromise or other mass effect and severe hypopituitarism, such as ACTH deficiency or panhypopituitarism. For the woman with panhypopituitarism and infertility, ovulation induction with gonadotropins is required, as discussed in other chapters. For men, fertility is restored with human chorionic gonadotropins (hCG) 1000 to 2000 units 2 to 3 times weekly to normalize testosterone, with recombinant FSH 25 to 75 IU 3 times a week added if necessary.58

Lymphocytic Hypophysitis Lymphocytic infiltration of the pituitary is a rare disorder, which most commonly occurs in postpartum women.59 Common presentations are headache with inability to lactate postpartum due to impaired prolactin production or polyuria and polydipsia from diabetes insipidus.60 Some women are relatively asymptomatic but develop amenorrhea or nonspecific symptoms of hypopituitarism over time. The pattern of pituitary deficiencies is highly variable and often follows a pattern much different from that observed with macroadenomas, such as ACTH and TSH deficiency with diabetes insipidus but preserved GH and gonadotropins. During the active phase, MRI shows a symmetrically enlarged pituitary and stalk that enhances markedly with gadolinium. After the damage has occurred and the disease has subsided, the MRI can show a partial empty sella. Methylprednisolone in the acute phase is sometimes effective,61 but pituitary function when lost rarely recovers. The immune-checkpoint inhibitor ipilimumab, a monoclonal antibody to the cytotoxic T lymphocyte antigen 4 (anti-CTLA-4), incites the development of lymphocytic hypophysitis in 10% to 15% of patients, with a male predominance.62,63 In contrast, nivolumab and other monoclonal antibodies to programmed cell death protein-1 (PD-1) only cause hypophysitis in 1% of cases. Headache and fatigue are common presenting features, and symmetrical pituitary enlargement is seen on MRI. TSH deficiency is the most common endocrinopathy, and primary thyroid dysfunction also occurs in up to 10% of patients64; consequently, both TSH and free T4 should be monitored in patients receiving ipilimumab. Secondary adrenal insufficiency and hypogonadism are also common but not GH deficiency. Although these patients are usually not pursuing pregnancy during treatment, ipilimumab can induce long-term cancer remission, and hypophysitis results in chronic endocrinopathies in the survivors.

Other Disorders Affecting the Pituitary Granulomatous diseases such as sarcoidosis65 and tuberculosis can involve the hypothalamus and pituitary, also causing

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central hypogonadism. Hypopituitarism can be the initial manifestation of sarcoidosis, while others have neurosarcoidosis with manifestations such as optic neuritis. MRI shows brisk enhancement of the meninges with or without hypothalamic and pituitary abnormalities. Other tumors also arise in the hypothalamus and pituitary, including germinomas and lymphomas. Carcinomas metastasize to the pituitary, primarily to the stalk. Diabetes insipidus is often a presenting manifestation, and hypogonadism is one of the most frequent manifestations of hypopituitarism in these neoplastic disorders. Hemochromatosis (primary or secondary) and amyloidosis are infiltrative diseases that cause hypopituitarism.66 The classic triad includes liver dysfunction, skin bronzing, and diabetes mellitus (“bronze diabetes”), but arthropathy, cardiomyopathy, and various endocrinopathies including adrenal insufficiency67 and hypogonadotropic hypogonadism68 are common as well. Iron deposition in the hypothalamus has predilection for impairing GnRH production among the releasing hormones. Hemochromatosis is one of the few disorders in which the male reproductive axis is more vulnerable to disruption than in the female, due to monthly menses in women. Some causes of hypopituitarism are geographical curiosities, such as hemorrhagic hypopituitarism following viper bites in Southeast Asia.69 Genetic causes of hypopituitarism are reviewed in Chapter 17.

Adrenal Disorders ◆ Specific features of Cushing syndrome include proximal

myopathy, nonblanching purple striae, dermal atrophy, and disproportionate fat accumulation in the head and neck. ◆ Glucocorticoid therapy for women with classic 21-hydroxylase deficiency (21OHD) seeking pregnancy should be titrated to achieve a follicular-phase progesterone <0.6 ng/mL (2 nmol/L). ◆ A basal or cosyntropin-stimulated 17-hydroxyprogesterone (17OHP) >1000 ng/dL (30 nmol/L) or CYP21A2 genotyping reliably diagnose nonclassic 21OHD among women with hirsutism and oligomenorrhea.

Overview The adrenal consists of a cortex, with three distinct zones, and a medulla. The medulla is an extension of the sympathetic nervous system and produces epinephrine. The steroidproducing cells of the cortex are arranged into the outermost zona glomerulosa, which produces aldosterone; the zona fasciculata, which produces cortisol; and the zona reticularis, which produces the androgen precursor DHEAS. DHEA and DHEAS are metabolized to testosterone in peripheral tissues, and the adrenal produces small amounts of androstenedione and testosterone.70 The adrenal also produces rather large amounts of 11β-hydroxyandrostenedione,71 primarily via the 11β-hydroxylation of androstenedione, which is metabolized to the potent androgens 11β-hydroxytestosterone and 11-ketotestosterone.72 ACTH is the primary regulator of cortisol and DHEAS production (see Fig. 24.1), whereas aldosterone synthesis is mainly stimulated by the reninangiotensin system and by potassium. Diseases of the adrenal gland causing hormone deficiency rarely interfere with reproduction directly, but certain hormone excess states contribute to infertility, particularly

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for women. In the male, the contribution of adrenal DHEAS and other 19-carbon steroids to circulating testosterone concentrations is normally small, but in women, a variable amount of testosterone and all 11-ketotestosterone normally derives directly from the adrenal or from adrenal-derived precursors.72 Consequently, disorders that increase adrenal DHEAS production cause hyperandrogenemia in women, which can impair fertility. Hypercortisolism may suppress gonadotropin production in women and, to a lesser extent, in men. We will not discuss primary aldosteronism, adrenal insufficiency, or pheochromocytomas in this chapter because these disorders rarely impair fertility in isolation.

Adrenal Disorders That Affect Reproduction Cushing Syndrome The Cushing syndrome is categorized as iatrogenic or endogenous, and endogenous Cushing syndrome is dichotomized as being ACTH-dependent or ACTH-independent (Table 24.2). The majority of Cushing syndrome is ACTHdependent, the most common cause being ACTH-producing pituitary tumors, which is called Cushing disease. The differential diagnosis of ACTH-dependent Cushing syndrome also includes ectopic production of ACTH or CRH by neuroendocrine carcinomas, most commonly small cell lung cancers, or by foregut neuroendocrine tumors, formerly called “carcinoid” tumors of the thymus, bronchus, or pancreas, as well as pheochromocytomas and medullary thyroid cancers.73 ACTH-independent Cushing syndrome is caused by unilateral adenomas or carcinomas and by bilateral

Table 24.2  Etiologies of Endogenous Cushing Syndrome ACTH-independent

Adrenocortical adenoma Adrenocortical carcinoma Macronodular hyperplasia Micronodular hyperplasia Corticotrope tumor (Cushing disease) Corticotrope hyperplasia Ectopic ACTH syndrome Ectopic CRH syndrome

ACTH-dependent

ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.

A

micronodular or macronodular hyperplasia. Cushing disease occurs most commonly in young women, and DHEAS production is more commonly elevated in ACTH-dependent forms of Cushing syndrome than in ACTH-independent forms. Consequently, Cushing disease in women is the most relevant form of hypercortisolism that impairs reproduction. The clinical manifestations of cortisol excess can be subtle in the early stage when the diagnosis is most difficult but the benefits of treatment and potential for full recovery the greatest. Cortisol is a catabolic hormone that causes lipolysis and fat redistribution, as well as breakdown of body tissues such as muscle, skin, and bone. Central obesity is a prominent and common feature, with disproportionate fat accumulation around the face and neck. The dorsocervical fat pad (“buffalo hump”) is a well-known feature of Cushing syndrome, but supraclavicular fat pads are more specific for this disorder, especially in an otherwise nonobese individual (Fig. 24.5). Facial and upper chest plethora is observed (see Fig. 24.5), and women often develop hirsutism. Proximal muscle weakness and skin thinning are two very specific features of Cushing syndrome, and osteoporosis in an obese individual should raise suspicion as well.73 Patients endorse difficulty arising from a chair and walking up stairs or getting out of a car, combing their hair, or changing an overhead light bulb. Skin thinning and capillary fragility cause easy bruising, and if weight gain is rapid, the striae formed are violaceous and nonblanching, reflecting hemorrhage into the new skin by fragile blood vessels. These striae are found on the abdomen and flanks, near the axillae, and on the thighs and breasts. If greater than 1 cm, purple striae are very specific for hypercortisolism; however, these findings develop late and only in reproductive-age women with severe disease. The most important scenario in which Cushing syndrome should be considered is in the young woman with oligomenorrhea and hirsutism, who could be mistaken for simple polycystic ovary syndrome (PCOS). A history of hirsutism onset after age 25 or specific findings for hypercortisolism, such as easy bruising, thin skin, proximal muscle weakness, and osteoporosis, should prompt screening for Cushing syndrome. The diagnosis of hypercortisolism can be difficult early in the disease because of the large overlap with normals. Testing is based on the principles that the cortisol production rate is increased,74 that the normal diurnal rhythm is

B Four years prior to diagnosis

Cushing diagnosed

FIGURE 24.5  Subtle clinical signs of Cushing syndrome. This woman is shown 4 years before diagnosis (A) and at the time of diagnosis (B). In (B), she demonstrates facial plethora and loss of clavicular silhouettes due to supraclavicular fat.



disrupted,75 and that cortisol is not suppressible.76 These principles are employed by the 24-hour urinary free cortisol,77 late-night saliva78 or serum cortisol measurements,75 and overnight dexamethasone suppression testing,79 respectively. The caveats of testing are beyond the scope of the chapter, but the reader should be aware that both false-positive and false-negative results are common. Consequently, tests often must be repeated several times before a diagnosis can be made or excluded. Once hypercortisolism is confirmed, an ACTH measurement will determine if the disease is ACTH-dependent or ACTH-independent. If ACTH-independent (ACTH <5 pg/ mL), an abdominal computed tomography scan of the adrenal glands is obtained. Patients with early ACTH-independent Cushing syndrome will have low but not suppressed ACTH (5 to 15 pg/mL), and these patients should have serial testing until the diagnosis is clarified.80 If the ACTH is normal or elevated, the next step is MRI of the pituitary with gadolinium contrast. The caveat of pituitary imaging is that small abnormalities of the pituitary are common, and about half of patients with Cushing disease lack a visible tumor by MRI. To conclusively exclude the ectopic ACTH syndrome, inferior petrosal sinus sampling is performed.81 Blood draining both sides of the pituitary is sampled from the inferior petrosal sinuses under ovine CRH stimulation (100 µg bolus), and the ACTH values in these specimens are compared with those obtained in peripheral blood drawn simultaneously. An ACTH step-up greater than three from peripheral blood to the inferior petrosal sinus is reliable evidence for a pituitary source of ACTH.82 Neuroendocrine tumors causing ectopic ACTH production are usually identified with cross-sectional imaging of the chest, abdomen, and pelvis, or with SS-receptor scintigraphy. The [68Ga]-DOTATATE or -DOTATOC PET scans are more sensitive than [111In]pentetreotide SPECT studies,83 but occult tumors are rarely identified with scintigraphy when cross-sectional imaging is negative.84 Treatment of Cushing syndrome is primarily surgical. Cushing disease is treated with transsphenoidal pituitary adenomectomy, yet even in the hands of experienced surgeons, long-term cure rates are not above 80%.82 Repeat surgery, radiotherapy, and even bilateral adrenalectomy may be recommended if disease persists. Medical management with metyrapone, ketoconazole, and trilostane has been employed but are seldom very effective in severe disease. Mifepristone at high doses blocks the glucocorticoid receptor and improves the catabolic and metabolic features of all forms of Cushing syndrome,85 but the renal and hemodynamic manifestations of hypertension and hypokalemia must be managed independently. Cabergoline is effective in reducing hypercortisolism for a small subset of pituitary tumors that express dopamine type 2 receptors.86 Furthermore, many corticotrope tumors express sst5 but not sst2, so while octreotide is rarely effective in reducing ACTH secretion, pasireotide reduces ACTH and cortisol production in the majority of cases.87 Apparently cured patients with Cushing disease can have recurrences many years later, and screening with late-night saliva cortisol is the most sensitive test to identify biochemical recurrence.88,89 In contrast, ACTH-independent Cushing syndrome is normally cured by unilateral or bilateral adrenalectomy, except in the case of adrenocortical carcinomas with inoperable or metastatic disease.

CHAPTER 24  Endocrine Disturbances Affecting Reproduction 601

Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency The manifestations of 21OHD in the infant as an intersex disorder were discussed elsewhere (see Chapters 4, 16, and 17), so this discussion will be restricted to adults with classic and nonclassic forms of 21OHD. Among the forms of CAH, 21OHD is by far the most common form, accounting for greater than 90% of cases.90 Classic 21OHD is caused by mutations in the CYP21A2 gene, which severely impair the activity of the encoded P450 21A2 enzyme to less than 2% of wild-type activity.91 Nearly all of these patients have clinical manifestations and require therapy with glucocorticoid and mineralocorticoid replacement. Milder mutations, particularly the V281L allele, cause nonclassic 21OHD (Table 24.3).92 Males with nonclassic 21OHD are rarely ascertained unless evaluation for premature pubertal features (body hair, acne, growth spurt) is sought. Females with nonclassic 21OHD present with hyperandrogenism, which manifests with hirsutism, acne, and irregular menses,93 but not all patients are symptomatic or require treatment. Similarly, patients with intermediate severity are often not diagnosed until adulthood, particularly males (Fig. 24.6). In many countries, 21OHD testing is part of newborn screening procedures, so most newborns are identified before adrenal crisis occurs, even if not ascertained by genital ambiguity. The diagnosis of 21OHD is based on elevated circulating concentrations of 21-deoxysteroids, in particular 17OHP. A random serum 17OHP greater than 10,000 ng/dL with serum cortisol less than 5 µg/dL establishes the diagnosis of classic 21OHD in males and females, and dynamic testing is rarely required.94 In the case of nonclassic disease, a morning serum 17OHP more than 200 ng/dL should prompt repeat measurement of cortisol and 17OHP 30 to 60 minutes after cosyntropin administration (250 mcg intravenous or intramuscular). Post-cosyntropin 17OHP values in the 1000 to 10,000 ng/dL range are typical of nonclassic 21OHD.95-97 If laboratory data are equivocal, genetic testing for mutations in the CYP21A2 gene on DNA from peripheral blood cells is available. The repertoire of mutations commonly found in 21OHD is limited due to the molecular mechanism responsible for most cases. The CYP21A2 gene is located in a duplicated locus within the HLA region on chromosome 6p that includes the genes for the fourth component of complement. In the duplicated region, the DNA corresponding to the CYP21A2 gene is replaced by the CYP21A1P pseudogene.98,99 This

Table 24.3  21-Hydroxylase Deficiency Form Classic Salt-wasting Simple virilizing† Nonclassic

Common Mutations Large deletions, 656A/C-G,* G110del8nt, Q318XR356W,* R483P, I236N+V237E+M239K 656A/C-G,* I172N, R356W* P30L, V281L, R339H, P453S

*Can be associated with either salt-wasting or simple virilizing disease. † All patients with classic 21-hydroxylase deficiency are prone to salt wasting with physiologic stress, but the most severely affected experience spontaneous salt-wasting crises in infancy.

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FIGURE 24.6  Computed tomography of adrenal glands in a woman with nonclassic 21-hydroxylase deficiency (21OHD) diagnosed at age 50. She had both severe hirsutism and rapid somatic growth in childhood with normal external genitalia. She menstruated regularly during her reproductive years and gave birth to three children without glucocorticoid or ovulation therapies. Screening laboratory values included a testosterone of 179 ng/dL, sex hormone binding globulin of 52 nmol/L, dehydroepiandrosterone sulfate of 427 µg/dL, adrenocorticotropic hormone of 16 pg/mL, and 17-hydroxyprogesterone (17OHP) of 1100 to 2500 ng/dL. The 17OHP rose to more than 17,000 ng/dL with cosyntropin stimulation, establishing the diagnosis of 21OHD. The enlarged but normallyshaped adrenal glands are indicated by arrows.

pseudogene contains several mutations that render the cognate mRNA and protein nonfunctional. Most cases of 21OHD derive from gene conversion events, in which some or all of the CYP21A2 gene is replaced by the corresponding region of the CYP21A1P pseudogene.100 Consequently, the spectrum of mutations and the worldwide prevalence of 21OHD is fairly consistent, but certain mutations are particularly common in specific populations, such as the intron 2 A-to-G mutation in Yupik Eskimos, which accounts for the high prevalence of classic 21OHD in that population.101 Occasionally, true point mutations are found instead.102 Heterozygous carriers are identified with confidence by genetic testing, whereas 17OHP values, even after cosyntropin stimulation, show broad overlap with normal individuals of either sex. The mechanisms of reduced fertility in women with classic 21OHD are complex, although affected women have given birth to normal female infants.103 Chronic hyperandrogenemia, even though largely adrenal in origin, contributes to chronic oligo-anovulation. In addition, many women with 21OHD develop a secondary PCOS, with characteristic ovarian morphology, thecal hyperplasia, and ovarian androgen excess as well.104 The block in 17OHP metabolism causes accumulation of adrenal-derived progesterone upstream of the enzymatic defect, and high circulating progesterone concentrations impair endometrial maturation and implantation.105 Overtreatment with synthetic glucocorticoids, however, can suppress gonadotropins and cause glucose intolerance with its attendant reproductive disturbances.106 Women with virilization of the external genitalia face additional impediments to fertility related to anatomical considerations. Vaginal stenosis, either prior to reconstruction surgery or following suboptimal surgery and/or dilation, is known to cause dyspareunia,107,108 which discourages

coitus.109,110 Vaginal anomalies also compromise sperm deposition, and high circulating progesterone concentrations inhibit sperm penetration and fertilization. Psychosocial influences should not be underestimated. The influence of prenatal and/or early androgen exposure, the psychologic adjustment to masculinization, and the presence of sexual dysfunction might all be significant factors contributing to gender identity and sexual preference women with CAH.111 Women with nonclassic 21OHD are most commonly identified during an evaluation of hirsutism, oligomenorrhea, or infertility mimicking PCOS. It is difficult to distinguish nonclassic 21OHD from idiopathic PCOS on clinical grounds93,112; therefore, guidelines suggest screening for nonclassic 21OHD with a 17OHP before making the diagnosis of PCOS.113 More careful studies suggest that the frequency of infertility or chronic anovulation in women with nonclassic 21OHD is not much higher than in the general population. Nevertheless, if infertility and/or chronic anovulation are present in a woman with nonclassic 21OHD, these women often benefit from glucocorticoid replacement when trying to conceive. Curiously, about 70% of women with nonclassic 21OHD in one large series are compound heterozygotes for one nonclassic and one classic allele,114 whereas the majority should be homozygous for nonclassic alleles given population estimates of carrier frequencies. This result suggests that the less severely affected nonclassic 21OHD patients rarely come to medical attention. Furthermore, cryptic and largely asymptomatic nonclassic 21OHD was found in 4% of parents with children affected by classic 21OHD,115 all of whom were heterozygous carriers of classic alleles. Little data exist to guide the optimal management of adults with 21OHD, either for long-term glucocorticoid replacement or for improving fertility.94,116 A range of treatment regimens are used without obvious rationale, although the convenience of once-daily dosing has favored use of the more potent glucocorticoids including prednisone, prednisolone, and dexamethasone.117 In a large audit of 21OHD patients in England, many were short and obese, with poor health metrics and quality of life, and overtreatment with glucocorticoids appeared to be common118; a natural history study at the National Institutes of Health revealed similar findings.119 Consequently, the minimum amount of glucocorticoid replacement to maintain testosterone in an acceptable range is recommended for chronic therapy in women, although this dose and target steroid values will vary among individuals. Serum 17OHP should not be normalized, as occurs with overtreatment, but dose adjustments should be based on serum testosterone and androstenedione values.120 Hydrocortisone is preferable for chronic therapy but must be given in at least two divided doses, although sustained-release preparations are in development,121-123 and continuous subcutaneous infusion is very effective but labor-intensive and off-label.124 Prednisolone and dexamethasone lower androgen production more effectively than hydrocortisone, particularly for the morning rise in ACTH and adrenal-derived steroids, where even bedtime hydrocortisone is not very effective. For classic 21OHD patients, fludrocortisone acetate in doses sufficient to normalize plasma renin activity and serum potassium, eliminate orthostasis, and maintain fluid balance, should be maintained throughout life with rare exceptions. Despite the many barriers to achieving pregnancy in women with 21OHD, fecundity rates in those women who attempt pregnancy are greater than 90%, equivalent to the general



population.125 The most critical parameter favoring conception appears to be follicular-phase serum progesterone, which should be lowered to less than 0.6 ng/mL (2 nmol/L) with multiple doses of hydrocortisone and/or prednisolone. A bedtime dose of 0.5 to 2 mg prednisolone, which is combined with either daytime hydrocortisone or prednisolone (one or two doses), appears to be particularly important for achieving pregnancy. Ovulation induction with standard methods and agents might be necessary despite optimal adrenal replacement regimens. Despite clinical features of PCOS shared with 21OHD, metformin and other insulin sensitizers have not been studied adequately in women with 21OHD. Prenatal treatment with dexamethasone has been shown to reduce fetal virilization in couples who have one or more children with 21OHD,126 but this treatment is considered experimental due to the paucity of long-term outcomes data in treated children with or without 21OHD.94 Almost all men with nonclassic 21OHD are asymptomatic and can be identified only with genetic testing. Men with classic 21OHD, in contrast, frequently develop infertility, particularly if poorly controlled. Severe adrenal androgen excess causes gonadotropin suppression with subsequent Leydig cell atrophy, reduced testicular testosterone production, and impaired spermatogenesis.127,128 Glucocorticoid replacement often normalizes testicular function, although high doses are often required initially. More commonly, testicular adrenal rest tumors (TARTs) are the cause of male infertility in 21OHD.129 The steroid-producing cells of the adrenal cortex and the gonads derive from the same pool of precursors during embryogenesis. The migration of adrenal cells to the suprarenal space can be imperfect, and adrenal cortex cells or progenitors appear to reside in the testis or within the groin and abdomen. ACTH is trophic for these adrenal rest cells as well, and when ACTH is high as in poorly controlled 21OHD, these cells will form masses, most often in the testis itself. TARTs are present in 30% to 60% of men with 21OHD, and their size correlates better with adrenal volume than with single steroid measurements.130 Testicular ultrasonography is the most sensitive method of diagnosis, although many are palpable.131 Because the testis is confined to a rigid capsule, the growth of TARTs impairs testicular blood flow and efflux of sperm into the ejaculate. Treatment of TARTs often requires potent glucocorticoids, such as dexamethasone, 1 to 2 mg at night,132 although even this therapy is not always successful in reducing tumor size and restoring fertility. Combination therapy with daytime hydrocortisone and low-dose (0.1 mg) bedtime dexamethasone also appears effective and less toxic than dexamethasone monotherapy at higher doses.133 Surgical resection of the TARTs by a competent urologist is associated with a low risk of recurrence but with little improvement in spermatogenesis or testosterone synthesis.134 This result, however, could reflect a selection bias in reserving surgery for the most severely affected men. The presence of TART and elevated serum FSH are poor prognostic factors for fertility in men with classic 21OHD.135,136

Other Congenital Adrenal Hyperplasia The other forms of CAH associated with androgen excess in women are 11-hydroxylase deficiency (11OHD) and 3β-hydroxysteroid dehydrogenase/isomerase deficiency (3βHSDD). In 11OHD, caused by mutations in the CYP11B1 gene that encodes P450 11B1, the 11-deoxysteroids

CHAPTER 24  Endocrine Disturbances Affecting Reproduction 603

11-deoxycorticosterone (DOC) and 11-deoxycortisol are markedly elevated, and excess DOC causes hypertension and hypokalemia, unlike 21OHD.137 Serum 17OHP may be elevated in 11OHD, but much less than in 21OHD with similar hyperandrogenemia. In 3βHSDD, caused by mutations in the HSD3B2 gene, the diagnostic steroid ratios are those of delta-5 to delta-4 steroids, such as 17-hydroxypregnenolone/ cortisol ratios greater than 6 standard deviations above normal.138 Note that circulating testosterone concentrations are paradoxically elevated in women with 3βHSDD. The delta-5 steroids DHEA and DHEAS are metabolized to active androgens in the periphery and converted to delta-4 steroids by 3βHSD type 1, which is abundant in liver and skin, explaining this phenomenon. The mechanisms responsible for infertility in men and women with 11OHD are similar to those in 21OHD. Treatments are similar, except that mineralocorticoid receptor antagonists (spironolactone, eplerenone) are useful to control hypertension during chronic therapy. Note that spironolactone is also an androgen receptor antagonist and is contraindicated in women who have unprotected intercourse. Women with 3βHSDD, even in the most severe cases, have mild clitoromegaly and little labioscrotal fusion, so anatomical impediments to pregnancy are less important, and high progesterone is less of a negative factor for reproduction than in 21OHD and 11OHD.138 Forms of CAH that impair both androgen and estrogen production include combined 17-hydroxylase/17,20-lyase deficiency,139 caused by mutations in the CYP17A1 gene encoding P450 17A1,140 and isolated 17,20-lyase deficiency,141 due to mutations in CYP17A1142,143 or its redox partner proteins cytochrome P450-oxidoreductase (POR mutation G539R)144 and cytochrome b5.145,146 Although all patients with complete 17OHD appear phenotypically as prepubertal females without treatment, those with 46,XX karyotype have chronic anovulation and as a result are prone to develop large cystic ovaries that can hemorrhage.147 These women can develop some secondary sexual characteristics and even cyclic menses if the enzymatic defect is incomplete.148,149 Nevertheless in vitro fertilization has been achieved with aspirated oocytes,150,151 and live triplets were reported after transfer of cryopreserved embryos in a patient with partial 17OHD.152 A term pregnancy in a woman with nearly complete 17OHD was described recently.153 Viable embryos were obtained from an initial superovulation and in vitro fertilization cycle, but she miscarried. The critical strategy during the second cycle—as also used in the case bearing live triplets—was to suppress both ovarian and adrenal-derived progesterone with GnRH agonist and dexamethasone, respectively, prior to endometrial preparation with estradiol valerate and implantation of frozen embryos. Estrogen treatment was stopped at 14 weeks, and the baby was delivered at 30 weeks. Lipoid CAH, due to mutations in the STAR gene encoding the steroidogenic acute regulatory protein (StAR)154 or rarely the CYP11A1 gene encoding P450 11A1,155 abrogates all steroid production, although a nonclassic form with partial StAR deficiency mainly impairs cortisol production.156 One 46,XX woman with lipoid CAH achieved pregnancy three times at age 25 to 30 following clomiphene stimulation and progesterone support, and the second and third pregnancies resulted in live twin and singleton births, respectively.157 POR deficiency manifests as a spectrum of phenotypes with

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disordered steroidogenesis,158 from primary amenorrhea in phenotypically normal women to the Antley-Bixler syndrome, with skeletal dysmorphologies.159,160 Patients with POR deficiency are generally considered infertile, although most of the patients diagnosed with this condition since its description in 2004 are children. Milder cases, in which pregnancies might be more likely than in more typical disease, are also less likely to be evaluated for this diagnosis.

Colloid Follicles

Thyroid Disorders ◆ The mechanisms for the association of subclinical hypothyroid-

ism and autoimmune thyroid disease with reduced fertility and miscarriage are unknown, and a benefit of thyroid hormone replacement is not proven. ◆ For hypothyroid women during pregnancy, the levothyroxine dose is usually increased by 10% to 50% within the first month of gestation, and monitored every 4 weeks in the first trimester using pregnancy-specific reference ranges for TSH and (free or total) T4. ◆ In a woman with Graves disease, thyroid-stimulating immunoglobulin titer should be measured in the third trimester because transplacental transfer can cause neonatal thyrotoxicosis in the baby.

Overview Before discussing the specific effects of thyroid disorders on reproductive function, it is important to understand some basic principles and potential areas of interaction between elements of thyroid hormone physiology and reproductive function. Within the thyroid gland, millions of follicles are the factories and storage silos for all of the circulating T4 and 20% of the active T3 thyroid hormone. The thyroid follicle is composed of simple secretory epithelial cells surrounding a lumen containing colloid—a gelatinous substance composed primarily of thyroglobulin and T4 (Fig. 24.7). The unique aspect of the thyroid gland is its ability to store enormous quantities of thyroid hormone in the follicular colloid. Iodide imported from the circulation and concentrated in colloid is used for iodination of the thyroglobulin backbone by thyroid peroxidase (TPO; Fig. 24.8) to produce inactive precursor mono- and diiodotyrosines. Synthesis of T4 and T3 using these precursors is also catalyzed by TPO. Reuptake and Tg digestion off of the stored T3 and T4 from the colloid allows for secretion through the basolateral membrane into the abundant capillary network. As described in the pituitary section overview, the hypothalamic-pituitary-thyroid axis is a straightforward model of an endocrine feedback system. The anterior pituitary secretes TSH, which regulates multiple steps in thyroid hormone production: (1) growth of the follicles, (2) iodine uptake, and (3) iodination of thyroid hormone by the secretory epithelial cells. Control of TSH secretion, and therefore, ultimate control of all elements required for thyroid hormone production, is tightly regulated by negative feedback of circulating T4 and T3, suppressing production of both TRH from the hypothalamus and TSH by the anterior pituitary (see Fig. 24.1A). Outside of the hypothalamic-pituitary-thyroid axis, the major regulator of thyroid hormone production is the

FIGURE 24.7  Histology of a normal thyroid gland. Shown is a 100× magnification of a hematoxylin and eosin-stained section of normal thyroid. Single-layer, epithelial-lined follicles of variable sizes are filled with pink colloid where thyroglobulin, triiodothyronine, and thyroxine are stored. Colloid

Capillary T4

T4

T4 T4 T3

T3

T3 T4 T4

T4 Tg

T4 Tg

T4

T4

Tg

T3

T3

T3

T4 Tg

ATP TSH

TPO cAMP

Tg Tg

Na

Na

I

NIS I

Basolateral

I

I

Tg

T3 I I I

I Pendrin

I

I Apical

FIGURE 24.8  Production of thyroid hormone in the follicular epithelial cell. This schematic illustrates the variety of functions carried out in the follicular epithelial cell from iodine (I) transport via the sodium (Na) iodide symporter (NIS), thyroglobulin (Tg) synthesis, iodination, and thyroxine (T4) production by thyroid peroxidase (TPO) at the apical membrane where Tg and Tg complexed with triiodothyronine (T3) and T4 are stored. Reuptake and Tg digestion from the complexes allows for secretion of T3 and T4 through the basolateral membrane into the abundant capillary network. Stimulation by thyrotropin of the thyroid-stimulating hormone (TSH) receptor results in cyclic AMP (cAMP) production, which augments hormone production by stimulating many cellular functions. ATP, Adenosine triphosphate.

concentration of thyroxine-binding globulin (TBG). Circulating T4 is almost entirely (99%) bound to plasma proteins— approximately 70% bound to TBG, 20% to transthyretin (prealbumin), and 10% to albumin. In women, significant changes in TBG glycosylation in the liver are induced by rises in estradiol during pregnancy or exogenous estrogens,



prolonging TBG half-life, and increasing circulating TBG concentrations.161 The rise in TBG can transiently decrease free T4 concentrations, leading to an increase in the TSH and total T4 to maintain normal free T4. During pregnancy, this may also lead to a visible enlargement of the thyroid gland or goiter. Peripheral conversion of T4 to T3 is mediated by deiodinases, types 1 and 2 located in different locations both at the tissue and cellular level. Interestingly, type 3 deiodinase is almost exclusively expressed in the placenta where it is tightly regulated by thyroid hormone concentrations.

Thyroid Disorders That Affect Reproduction Diseases of the thyroid are more common in women than men. The most common conditions are Hashimoto thyroiditis and Graves disease, both autoimmune diseases of the thyroid. Despite the importance of thyroid hormone in maintaining normal organ and endocrine function throughout the body, the exact mechanisms for thyroid hormone’s effects are not well understood. Notably, it is the absence of thyroid hormone (hypothyroidism) and the multitude of accompanying symptoms that demonstrates its importance throughout the body. Similarly, for reproduction, hypothyroidism has more significant effects on menstrual cycles and fertility than hyperthyroidism, or more generally, thyrotoxicosis. Hypothyroidism may exert more of an effect on reproduction through decreased feedback to the hypothalamic-pituitary axis, subsequent hyperprolactinemia, and interference with GnRH pulsatility and ovulation. The effect of low and high thyroid hormone concentrations on reproduction may also be mediated indirectly by effects on sex hormone binding globulin (SHBG) function and production as well as directly on steroidogenesis and sperm morphology, production, or function.162 Subclinical hypothyroidism and autoimmune thyroid disease have been associated with decreased fertility and miscarriage, although the mechanism and benefit from treatment with thyroid hormone replacement are still not clear.163-165

Hypothyroidism The overall prevalence of hypothyroidism is 3.1% in reproductive age women.166 Women with hypothyroidism present with any of numerous symptoms and signs (Table 24.4). The reproductive age woman may experience irregular menses, anovulatory cycles, or menorrhagia, or they may present only with infertility.162 A significant mechanism for alterations in the reproductive system is through the hypothalamic-pituitary axes. While basal gonadotropins are normal, elevated TRH can stimulate lactotrophs to produce prolactin, which interferes with GnRH pulsatility as described earlier in the pituitary section. In women and men, hypothyroidism reduces SHBG binding affinity through altered sialic acid content, which reduces total and often free fractions of estrogens and androgens167; conversely, hyperthyroidism increases SHBG production.168 Hypothyroidism may also interfere with ovarian function. Experimentally, T4 has been shown to stimulate ovarian steroidogenesis in granulosa cells cultured in vitro.169 In men, hypothyroidism has been associated with decreased libido, erectile dysfunction, and abnormalities of sperm morphology or motility.162 As opposed to women, the hypogonadotropic hypogonadism associated with hypothyroidism is not associated with hyperprolactinemia, but

CHAPTER 24  Endocrine Disturbances Affecting Reproduction 605

Table 24.4  Common Clinical Presentations of Thyroid Disorders Hypothyroidism

Hyperthyroidism

Weight gain Fatigue, Lethargy Constipation

Weight loss Fatigue, Irritability Increased frequency of bowel movements Heat intolerance Anxiety Dyspnea on exertion Palpitations Diaphoresis Lid lag or “stare” Tremor Hyperreflexia Supraventricular arrhythmias

Cold intolerance Hair loss Menorrhagia Infertility Dry skin Periorbital edema Hoarseness Delayed reflex relaxation phase Anemia

the hypogonadism can correct after thyroxine replacement.170 Abnormalities of sperm count, motility, and morphology as well as erectile dysfunction and poor testosterone response to hCG injections also improve after T4 replacement.171,172

Subclinical Hypothyroidism and Autoimmune Thyroid Disease While more severe hypothyroidism clearly interferes with ovulation and fertility, more subtle abnormalities of the pituitary-thyroid axis or the underlying autoimmune disease may also affect fertility. Subclinical hypothyroidism during pregnancy has been associated with adverse pregnancy outcomes, including miscarriage, gestational hypertension and diabetes, preterm delivery, and decreased IQ of the children. However, there remains little evidence to support universal screening before or early in pregnancy since initiating thyroxine replacement with a universal screening approach did not improve outcomes in a large randomized controlled trial.173 Debates exist about the study design of the universal screening trial that might have affected the ability to see an effect. Nevertheless, current guidelines from the Endocrine Society, AACE, and ACOG support a case finding versus universal screening approach in early pregnancy and preconception.174 In women being evaluated and treated for infertility, smaller trials support initiation of levothyroxine replacement when TSH levels are greater than 4 for improved pregnancy rates and decreased miscarriage rates. The role of anti-TPO antibodies in infertility is also unclear. Although subclinical hypothyroidism and thyroid autoimmunity are both associated with impaired fertility,175 the association with anti-TPO antibodies could be confounded by subclinical hypothyroidism or associated autoimmunity. There are also reported associations of anti-TPO antibodies with folliculogenesis, lower fertilization and pregnancy rates, and embryo quality; however, the underlying pathophysiology is yet to be determined.176 The role and potential benefit of thyroxine replacement in these women is still not firmly established.177 Few studies have investigated the role of subclinical hypothyroidism in male reproduction. In one study, men with subclinical hypothyroidism had the same hypogonadotropic hypogonadal profile as hypothyroidism, but there was no association with changes in sperm quality.178 Multiple studies have reported an association of antithyroid antibodies and miscarriage and preterm birth in euthyroid

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women.164,179 However, it is not clear whether this association represents a more generalized autoimmunity or a need for thyroid hormone replacement. There are only two small studies with T4 replacement in euthyroid women with antithyroid antibodies, with two meta-analyses in disagreement whether there is a significant risk reduction of miscarriage and preterm delivery with treatment.164,165,180,181 Until a large, randomized placebo-controlled trial provides stronger evidence of a treatment effect, T4 replacement is not recommended to prevent miscarriage in women with anti-TPO antibodies if they are euthyroid. T4 treatment should only be considered in women with anti-TPO antibodies who have subclinical or clinical hypothyroidism.163 The most common cause of hypothyroidism is chronic autoimmune thyroiditis (Hashimoto thyroiditis). In addition to Hashimoto thyroiditis, hypothyroidism may also be seen in patients with acute (silent) and subacute thyroiditis (Table 24.5). Postpartum thyroiditis is an acute thyroiditis that occurs within 6 months of delivery and is usually self-limited. Thyroiditis typically has an acute thyrotoxic phase followed by a hypothyroid recovery phase and eventually a euthyroid phase. Postpartum thyroiditis typically presents with symptoms in the hypothyroid phase, whereas subacute thyroiditis presents with pain during the hyperthyroid phase. Although most return to a euthyroid state in the short term, 20% to 64% of these women will develop chronic hypothyroidism over the next few years.182 An important secondary cause of hypothyroidism is radioactive iodine ablation or thyroidectomy for definitive treatment of Graves disease, thyroid nodules, or thyroid cancer. The diagnosis of hypothyroidism itself is easily made with modern immunoassays. Clinical hypothyroidism is defined by both higher than normal TSH and lower than normal free T4 concentrations. An elevated TSH greater than 10 mIU/L is a clear indicator of hypothyroidism with very rare exceptions (Fig. 24.9). Subclinical hypothyroidism describes the mild or early changes when the TSH rises before the free T4 falls below normal. The mild elevation in TSH compensates for the early decline in T4 production by the thyroid gland. During pregnancy, trimester-specific and lab-specific reference ranges should be used to determine the optimal TSH range and the diagnosis of clinical hypothyroidism.163 Although not necessary for the diagnosis of hypothyroidism, additional tests of anti-TPO and antithyroglobulin antibodies may influence treatment decisions by establishing underlying Hashimoto thyroiditis. The presence of anti-TPO antibodies increases

the risk for developing clinical hypothyroidism from 2.1% to 4.3% per year.183 Age and female gender also increase the risk of progression to overt hypothyroidism. The treatment of hypothyroidism involves replacement of thyroid hormone with synthetic T4 (levothyroxine). A general guide for replacement is a weight-based dose of 1.6 µg/kg once daily, but actual requirements may vary. After initiation or dose adjustment, follow-up tests should be ordered after at least 6 to 8 weeks. To minimize problems with absorption, levothyroxine should be taken without other drugs, especially calcium or iron-containing tablets. For the woman known to have hypothyroidism prior to pregnancy, very close monitoring of the TSH is required to maintain a euthyroid state given the increase in TBG and therefore total T4 requirements. This dose increase is particularly important for the fetus, with strong evidence that maternal hypothyroidism may affect fetal intellectual development during the first trimester when the fetus is dependent on maternal thyroid hormone.184 Maternal hypothyroidism and subclinical hypothyroidism are associated with a higher risk for miscarriage, hypertension in pregnancy, low birth weight from premature delivery,185,186 and gestational diabetes.187 Guidelines suggest achieving a target of TSH less than 2.5 µU/mL before pregnancy to lower the risk for maternal hypothyroidism in the first trimester.163,188 The T4 dose usually needs to be increased by anywhere from 10% to 20% to as high as 30% to 50% within the first month of gestation, and therapy should be monitored at least every 4 weeks in the first trimester after any adjustment.163,189

Hyperthyroidism Women and men with hyperthyroidism present with typical findings of weight loss, palpitations, anxiety, and increased frequency of bowel movements. For women, although oligomenorrhea and amenorrhea may be more common in women with hyperthyroidism than euthyroid women, there is less evidence of ovulatory dysfunction and infertility in hyperthyroidism than hypothyroidism. Fewer studies have evaluated reproductive function in hyperthyroid women. Hyperthyroidism is associated with increased SHBG and estrogen concentrations. Abnormalities in basal and stimulated gonadotropins have been observed in women with hyperthyroidism, which reverses after treatment for hyperthyroidism.162 During pregnancy, there can be subtleties to the diagnosis of thyrotoxicosis and distinguishing hyperthyroidism from

Table 24.5  Common Causes of Thyroid Disorders Primary Hypothyroidism

Primary Hyperthyroidism

Chronic autoimmune thyroiditis (Hashimoto) Radioiodine ablation Thyroidectomy Silent/postpartum thyroiditis (hypothyroid phase) Subacute thyroiditis (hypothyroid phase) Iodine deficiency Drugs (thionamides, lithium)

Graves disease Toxic multinodular goiter Solitary toxic nodule Silent/postpartum thyroiditis (lymphocytic) Subacute thyroiditis (granulomatous) Iodine-induced (e.g., amiodarone) Exogenous thyroid hormone ingestion

↓ TSH ↓ Free T4

Normal TSH

Central hypothyroidism Nonthyroidal illness Drug effect

Normal Free T4

Subclinical thyrotoxicosis Nonthyroidal illness T3 thyrotoxicosis

↑ Free T4

Thyrotoxicosis

Normal

↑ TSH Primary hypothyroidism

Subclinical hypothyroidism

TSH-secreting pituitary adenoma Thyroid hormone resistance syndrome Familial dysalbuminemic hyperthyroxinemia

FIGURE 24.9  Differential diagnosis of thyroid disorders based on thyroid-stimulating hormone (TSH) and free T4 results.



normal physiologic changes, hyperemesis gravidarum, and gestational trophoblastic disease. As opposed to association of antithyroid antibodies with fertility and miscarriage rates, the thyroid receptor stimulating antibodies of Graves disease have more of an impact on the fetus and the risk for neonatal thyrotoxicosis.163 In men with Graves disease, symptomatic hypogonadism and bioavailable testosterone lower than normal controls have been observed despite the overall increase in total testosterone and SHBG. These findings have been associated with impaired gonadotropin response to hCG and significant abnormalities in semen quality. Changes in semen parameters could be reversed with antithyroid treatment.190 Older men are more likely to be clinically affected because of a lower gonadal reserve to compensate for the increases in SHBG. Elevated estradiol may result in gynecomastia and also likely explains the normal gonadotropin concentrations with low free testosterone.162 Graves disease is the most common cause of hyperthyroidism. In addition to the symptoms of thyrotoxicosis and goiter, patients may present with the typical stare and extraocular muscle paralysis resulting from infiltrative orbitopathy and ophthalmopathy. Graves disease is an autoimmune disease with the thyroid-stimulating immunoglobulin (TSI) or antiTSH receptor antibody driving unregulated stimulation of thyroid hormone production. Thyroiditis refers to any inflammatory state of the thyroid. The thyrotoxicosis of thyroiditis results from release of stored thyroid hormone, which may persist for up to 2 months. As discussed above, the usual course is then transient hypothyroidism followed by recovery of thyroid function, although chronic hypothyroidism may also develop. Subacute (de Quervain) thyroiditis is distinguishable by a history of neck pain and recent viral infection and physical findings of fever and exquisitely tender thyroid. The serum thyroglobulin is often elevated in thyroiditis, and the erythrocyte sedimentation rate is particularly elevated in subacute but not silent thyroiditis. Other potential causes of thyrotoxicosis include an autonomous thyroid nodule and multinodular goiter. Toxic adenoma, which is less common than Graves disease or toxic multinodular goiter, is usually a benign, solitary tumor with autonomous T4 and T3 production. In a large proportion of toxic adenomas, a somatic or germline mutation in the genes encoding the TSH receptor or G protein subunits results in constitutive activation of TSH receptor signaling.191 Multinodular goiter is less likely to cause hyperthyroidism in reproductive age women and is more common in older patients. Growth and the development of autonomous function take years to manifest as hyperthyroidism, and most toxic adenomas are greater than 3 cm in diameter. The diagnosis of thyrotoxicosis is clear with an elevated free T4 and low TSH. However, a low TSH with a low or normal free T4 has several additional diagnoses to consider other than subclinical hyperthyroidism (see Fig. 24.9). Diagnosis of thyrotoxicosis during pregnancy should be made more cautiously than hypothyroidism, because the TSH level can be low in the first trimester due to hCG-mediated thyroid stimulation. Because total T4 is elevated due to the increased TBG during a normal pregnancy, pregnancy-specific ranges for total T4 should be used. Alternatively, free T4

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concentration can be measured and will only be elevated above nonpregnant ranges in overt hyperthyroidism. Radioactive iodine scans are not necessary to make the diagnosis of hyperthyroidism but are most useful for distinguishing Graves disease from toxic adenoma (Fig. 24.10), thyroiditis, and factitious disorder. Usually, clinical factors obviate the need for diagnostic scans. Especially since radioactive iodine scans are contraindicated during pregnancy, another useful test is the TSI or thyroid receptor antibody (TRAB). Elevated TSI or TRAB supports the diagnosis of Graves disease and is recommended for measurement in the week 20 to 24 of pregnancy to determine the need for increased fetal monitoring. In pregnancy, breastfeeding, or women trying to conceive, ultrasonography with Doppler blood flow may be useful for distinguishing Graves disease from thyroiditis. The need for experienced technicians and radiologists, however, limits the ability to recommend the general use of ultrasonography for this purpose.163 The pharmacologic treatment of Graves disease is antithyroid treatment with a thionamide—typically propylthiouracil (PTU) from 50 mg tid to 100 mg qid or methimazole 5 to 40 mg per day in one or two divided doses, although thionamide doses twice as high are used for the first few days or weeks in severe or life-threatening thyrotoxicosis. The goal of therapy initially is a T4 in the normal range, as the TSH rise may lag behind. Patients may experience a sustained remission after 12 to 18 months of therapy. Elevated T4 from thyroiditis is both transient and will not respond to antithyroid treatment. Symptoms of palpitations, anxiety, and tremor can be managed with a beta-blocker such as propranolol or metoprolol. In the case of subacute painful thyroiditis, pain responds to nonsteroidal antiinflammatory drugs or a course of corticosteroid therapy. Thionamides are useful for restoration of euthyroidism in patients with toxic adenomas and multinodular goiters, but usually definitive therapy (see later) is required. Radioactive iodine-131 ablation is an alternative to antithyroid agents for hyperthyroidism (aside from thyroiditis). When counseling reproductive age women and men about ablation, there is no evidence that previous radioactive iodine ablation at low doses used for hyperthyroidism will affect subsequent fertility in women or men or increase the risk for congenital abnormalities.162,163,192 In higher doses used for thyroid cancer remnant ablation, radioactive iodine may be associated with azoospermia, and sperm cryopreservation should be discussed with young men to preserve fertility for the first few months to years after therapy.162 Otherwise, guidelines suggest women wait at least 6 months after ablation to ensure that target TSH values are obtained on T4 replacement therapy.163 Methimazole is the preferred antithyroid treatment for hyperthyroidism over PTU due to concerns of hepatotoxicity. One important exception is the first trimester of pregnancy because of the rare association of methimazole with congenital abnormalities. After the first trimester of pregnancy, it is recommended that pregnant women are switched to methimazole for the remainder of the pregnancy.163,193 In practice, methimazole is often used throughout pregnancy if unable to successfully control T4 concentrations with PTU due to tolerability and efficacy issues. The goal for therapy in hyperthyroidism prior to conception or while pregnant is

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PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

A

B

FIGURE 24.10  Radioactive iodine-123 scans to distinguish Graves disease from toxic adenoma. (A) Increased radioactive iodine uptake seen symmetrically throughout a thyroid gland with Graves disease. (B) Increased uptake by a toxic adenoma, indicated by arrow, with little uptake elsewhere. The dotted lines approximate the outline of the thyroid gland with minimal uptake in comparison to the adenoma.

a free T4 at or slightly above the upper limit of the normal range to avoid hypothyroidism.163 Surgery—thyroidectomy or resection of a toxic adenoma— is generally reserved for treating hyperthyroidism in disease refractory to medical therapy, for glands that are producing obstructive symptoms, for large nodules, and when radioactive iodine is contraindicated or refused. In pregnancy, surgery is reserved for cases when disease is severe and refractory to medical therapy, or when antithyroid agents cannot be used due to the side effect of agranulocytosis or liver damage.

Top References American College of Obstetricians and Gynecologists: Practice Bulletin No. 148: Thyroid disease in pregnancy. Obstet Gynecol 125(4):996–1005, 2015. Auchus RJ: Management considerations for the adult with congenital adrenal hyperplasia. Mol Cell Endocrinol 408:190–197, 2015. Casteràs A, De Silva P, Rumsby G, et al: Reassessing fecundity in women with classical congenital adrenal hyperplasia (CAH): normal pregnancy rate but reduced fertility rate. Clin Endocrinol (Oxf) 70:833–837, 2009. Colao A, Abs R, Barcena DG, et al: Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study. Clin Endocrinol (Oxf) 68(1):66–71, 2008. Daly AF, Tichomirowa MA, Beckers A: The epidemiology and genetics of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 23(5):543–554, 2009. Feldthusen AD, Pedersen PL, Larsen J, et al: Impaired fertility associated with subclinical hypothyroidism and thyroid autoimmunity: the Danish General Suburban Population Study. J Pregnancy 2015:132718, 2015.

Finkielstain GP, Kim MS, Sinaii N, et al: Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 97(12):4429–4438, 2012. Howlett TA, Willis D, Walker G, et al: Control of growth hormone and IGF1 in patients with acromegaly in the UK: responses to medical treatment with somatostatin analogues and dopamine agonists. Clin Endocrinol (Oxf) 79(5):689–699, 2013. King TF, Lee MC, Williamson EE, et al: Experience in optimizing fertility outcomes in men with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. Clin Endocrinol (Oxf) 84(6):830–836, 2016. Lazarus JH, Bestwick JP, Channon S, et al: Antenatal thyroid screening and childhood cognitive function. N Engl J Med 366(6):493–501, 2012. Melmed S, Casanueva FF, Hoffman AR, et al: Diagnosis and treatment of hyperprolactinemia: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 96(2):273–288, 2011. Nieman LK, Biller BM, Findling JW, et al: Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 100(8):2807–2831, 2015. Speiser PW, Azziz R, Baskin LS, et al: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 95(9):4133–4160, 2010. Stagnaro-Green A, Abalovich M, Alexander E, et al: Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21(10):1081–1125, 2011. Turcu AF, Nanba AT, Chomic R, et al: Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur J Endocrinol 174(5):601–609, 2016.

References See a full reference list on ExpertConsult.com.

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