Endocrine Disturbances Affecting Reproduction

Overview

As the “master gland,” the anterior pituitary gland controls the function and products of other major endocrine glands, including the thyroid (releasing thyroxine [T ₄ ] and triiodothyronine [T ₃ ]), adrenal cortex (cortisol, dehydroepiandrosterone sulfate [DHEAS]), and gonads (predominantly estradiol plus progesterone in females and testosterone [T] in males). The anterior pituitary gland also produces growth hormone and prolactin, which act directly on target organs. The actions of growth hormone (somatotropin, 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/or inhibitory factors influencing pituitary hormone secretion

• 3.

  Hypothalamic factor pulsatility, leading to a 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. 25.1 .

Of the pituitary axes, the thyroid axis is the simplest for several reasons. The primary product of the thyroid is T ₄ , which is a precursor of the active hormone triiodothyronine T ₃ . Since T ₄ is heavily protein-bound, it has a long half-life (7 days) and is slowly metabolized to T ₃ . This scenario provides steady, well-dampened feedback, causing the thyroid axis to show high stability and low pulsatility. Hypothalamic thyrotropin-releasing hormone (TRH) pulses stimulate the release of thyroid-stimulating hormone (TSH); however, negative feedback by T ₃ , primarily the pool generated via deiodination of circulating T ₄ 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.

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 corticotropin-releasing hormone (CRH) and negative feedback by cortisol. Both vasopressin and various cytokines increase the production of corticotropin (ACTH) in response to stress or illness. As a consequence, this intricate feedback system provides a more responsive axis to physiological changes and needs. This level of sophistication, however, complicates clinical testing.

The GH 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 physiologic stressors, including hypoglycemia, also increase GH secretion.

Prolactin is the only anterior pituitary hormone that is primarily under negative control, mediated by dopamine from neurons in the arcuate and periventricular nuclei of the hypothalamus. 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 25.1 ). 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, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), and their regulation by gonadotropin-releasing hormone (GnRH) are discussed in detail for the male and female in other chapters. Here, we 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 below.

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 >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 lastly, ACTH. 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, ^, 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. In the following discussion, both the nature of the pituitary disorder and its treatment are addressed as they affect strategies for restoring reproductive function.

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. Hyperprolactinemia has many potential etiologies ( Table 25.1 ). 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.

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. Falsely elevated prolactin measurements can be caused by the presence of macroprolactin, also known as “big-big prolactin,” which is a complex of prolactin and IgG detected variably in different immunoassays but lacking normal biological activity. ^, If the prolactin is persistently elevated and causes other than pituitary tumors are excluded, a dedicated MRI of the pituitary sella with gadolinium contrast agent should be performed.

Microprolactinomas (tumors < 1 cm in greatest diameter) are found in about 1% of women aged 20 to 40 years old. The degree of prolactin elevation is roughly proportional to the size of the tumor. A tumor not secreting prolactin might cause hyperprolactinemia via stalk compression and impaired dopamine delivery, but the prolactin rarely if ever rises above 250 ng/mL. For example, a patient with a 3 cm pituitary mass and a prolactin of 150 ng/mL 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 is an immunometric assay artifact that lowers the reported value. 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. 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. 25.2 ). 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. 25.3 ), 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). Even for large and invasive macroprolactinomas with visual changes, tumor shrinkage by dopamine agonists can be immediate and effective ( Fig. 25.3 ). Treatment options are selected based on symptoms, tumor size, and patient goals. 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. ^, 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, irregular menses, low risk of tumor growth, and without galactorrhea or desire for pregnancy.

Bromocriptine is administered in 2 to 3 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, although low doses might be sufficient for mildly elevated prolactin concentrations. Cabergoline, administered at 0.25 to 2 mg once or twice weekly, is much more potent and better tolerated than bromocriptine. Goals of therapy include normalized serum prolactin and symptom relief. If pregnancy is not desired, contraception should be used with the first dose because fertility can be immediately restored. Bromocriptine is generally preferred if pregnancy is desired, stopping the medication upon confirming conception. Cabergoline use early in pregnancy was not found to increase the risk for miscarriage or fetal malformations and is generally considered safe also. For macroprolactinomas, especially with suprasellar extension, visual fields should be monitored throughout pregnancy and during lactation. MRI without contrast is performed only if tumor growth is suspected to affect vision or hemorrhage suspected due to severe headache and/or development of hypopituitarism. Cabergoline can be restarted to prevent vision compromise.

In some cases, particularly those in which the tumor has become no longer visible on an MRI scan, cabergoline can be discontinued after 2 to 5 years without recurrence of hyperprolactinemia. Chronic treatment with high doses of cabergoline for Parkinson disease has been rarely associated with cardiac valve disease ^, due to the serotonin receptor agonism by cabergoline but not bromocriptine. An approximately three-fold increased prevalence of asymptomatic mild or moderate tricuspid regurgitation was detected via echocardiogram in cabergoline-treated prolactinoma patients compared to controls, particularly at higher cumulative doses. Therefore, guidelines recommend regular echocardiograms in patients treated with high doses of cabergoline. Some societies further recommend baseline and regular surveillance echocardiograms in all patients receiving dopamine agonist therapy.

Surgery and radiotherapy are reserved primarily for rare tumors unresponsive to dopamine agonists and for patients intolerant to these drugs.

Surgery is most effective for microadenomas, with success rates approaching 90% for microadenomas but only about 60% for macroprolactinomas. ^, An immediate postoperative prolactin of less than 2 ng/mL is reliable evidence of cure. Radiotherapy typically takes at least a year to lower the prolactin significantly and stop tumor growth. Resumption of ovulatory cycles and spontaneous conception have been reported after gamma knife radiosurgery.

Occasionally, women 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. 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 self-testing 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. 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. Men presenting with hypogonadism might have very low testosterone concentrations and/or other evidence of hypopituitarism, which prompts pituitary imaging. Galactorrhea is rare but seen if 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 sufficiently prolonged that testicular atrophy has occurred. The erectile dysfunction of hyperprolactinemia does not always improve with testosterone replacement unless the prolactin is normalized. ^, Sperm count is not immediately restored by dopamine agonist therapy and may not return to normal until 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), and 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 co-secrete GH and prolactin also exist, which complicates the evaluation. Prolactin co-secretion does not predict an improved response to dopamine agonist therapy.

A serum IGF1, corrected for sex 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 females ) is used mainly to gauge response to therapy when IGF1 is equivocal, using a value of <0.4 ng/mL as remission. Gigantism occurs when the tumor forms prior to closure of the epiphyses. ^, Genetic causes of acromegaly and gigantism include multiple endocrine neoplasia type 1 (MEN 1, MEN1 gene), Carney complex ( PRKA1A gene), familial isolated pituitary adenoma (FIPA, AIP gene), and X-linked acromegaly and gigantism (X-LAG) ( GPR101 gene).

Combined modality therapy is the norm for the typical invasive somatotropinoma ( Fig. 25.4 ). Large tumors often require both transsphenoidal surgery and sometimes craniotomy to debulk the tumor sufficiently for drug or radiotherapy, whereas for microadenomas, cure rates are higher and hypopituitarism infrequent for experienced pituitary neurosurgeons. Pure somatotropinomas occasionally respond to high doses of dopamine agonists with reduced GH secretion and/or tumor shrinkage. Many somatotropinomas express somatostatin receptors, primarily type 2 (sst2), and remain responsive to somatostatin 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 somatostatin agonist therapy. ^, Some tumor shrinkage occurs in over half of somatotropinomas treated with somatostatin analogs, but the degree of regression is not as dramatic as for prolactinomas treated with dopamine agonists. Pegvisomant, a growth-hormone receptor antagonist that is modified with polyethylene glycol, normalizes IGF1 in up to 95% of patients during the initial trials, with long-term success rates of 60% to 65%. The drug is given via subcutaneous injection of 40 mg as loading dose, followed by 10 to 30 mg/day, and 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. ^, 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.

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.

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, but the glycoprotein products are biologically inactive due to improper glycosylation, dimerization and assembly. 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 three times a week added if necessary.