7 Endocrine disease and pregnancy

7 Endocrine disease and pregnancy M. R. JOHNSON A. M. McGREGOR

From the time of conception the development of the endocrine and reproductive systems are interdependent. Reproductive maturity and fertility depend on control of ovarian function by pituitary gonadotrophins. Following conception, pregnancy in turn induces hormonal changes necessary, not only for the maintenance of the pregnancy, but also for labour and lactation. Simultaneously pregnancy alters the function of elements of the endocrine system that are not directly related to maintenance of pregnancy. During the postnatal period the involution of pregnancy-induced changes and the onset of lactation are accompanied by fluctuations in circulating hormone l!evels and alterations in the immune system that are associated with specific endocrine disorders. In this chapter, endocrine diseases will be considered both as they impair fertility and as they impinge upon pregnancy. The close relationship between the reproductive and endocrine systems is liable to be disrupted by an endocrine disease and amenorrhoea and infertility often result. The combination is commonly seen in both the polycystic ovary syndrome and hyperprolactinaemia, but may also be found in thyroid, adrenal and pituitary disorders. Endocrine diseases are rare during pregnancy bull can have a devastating effect on its outcome; their recognition and appropriate management is therefore essential. POLYCYSTIC OVARY SYNDROME AND VIRILIZING

CONDITIONS The polycystic ovary syndrome (PCOS) lies at the other end of a spectrum of disorders which range from idiopathic hirsutism; both are characterized by the symptoms and signs of androgen excess. They have symptoms in common with but are aetiologically distinct from the virilizing conditio~Ls of congenital adrenal hyperplasia, androgen-secreting tumours and Cushing's syndrome. The clinical presentation of PCOS is varied but the majority of patients are infertile with menstrual irregularity, hirsutism, acne and greasy skin. The typical biochemical abnormalities are a raised testosterone, decreased sex hormone-binding globulin (SHBG) and raised serum luteinizing Bailli~re's Clinical Endocrinology and Metabolism-313 Vol. 4, No. 2, June 1990 Copyright © 1990, by Bailli6re Tindall ISBN 0-7020-1463-X All rights of reproduction in any form reserved

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hormone (LH) with an increased oestrone and normal oestradiol level; prolactin levels may be normal or mildly raised. The hypothalamopituitary axis is thought to be intact and recent evidence is suggestive of a primary ovarian abnormality. The aetiology of PCOS is fully discussed in a recent review (Franks, 1989). Stein and Leventhal initially advocated ovarian wedge resection in the management of PCOS (Stein, 1964) but this treatment has now largely fallen from use. In overweight women with PCOS, weight loss alone may bring about the return of ovulatory cycles and improvement in hirsutism (Pasquali et al, 1989). In non-obese patients the management varies with the presenting complaint. Fertility can usually be restored by the induction of ovulation using anti-oestrogens. Hirsutism, where possible, should be managed with local measures alone',. The combination of oestrogens and antiandrogens is effective, but will of course prevent ovulation and is therefore inappropriate treatment in women with PCOS who wish to ge pregnant; Congenital adrenal hyperplasia ( C A H ) i s a collection of inherited disorders of adrenal steroidogenesis due to various enzyme deficiency states. Its incidence is between 1 in 5000 and I in 10 000 of livebirths. Partial enzyme defec" forms of C A H may present later (they have even been diagnosed in o~d age) and need to be considered as a cause of hirsutism and menstrual irregularity within the PCOS-idiopathic hirsutism Spectrum of disorders. Late onset of C A H (LOAH) is characterized by menstrual disturbance with varying degrees of virilism. Studies have revealed a prevalence of 21-hydroxylase deficiency L O A H in hyperandrogenic women of between 1 and 6%. A single estimation of unsuppressed basal foUicular phase 17-hydroxyprogesterone (17-OHP) has recently been demonstrated to be an effective screening test of the hyperandrogenic women (Azziz and Zacur, 1989). In suspected L O A H , confirmation is achieved with a 17-OHP Synacthen (tetracosactrin) stimulation test, the 30 minute poststimulation being the critical value (Azziz and Zacur, 1989). Management is dependent on the enzyme defect and hence the hormone deficiency. Clearly, when virilism is combined with a salt-losing state, both fludrocortisone and corticosteroid are required. In the simple virilizing form, corticosteroids alone are sufficient as long as the plasma renin activity (PRA) is normal. If the PRA is elevated, optimum hormonal control is achieved with the addition of fludrocortisone. The replacement should be sufficient to maintain a normal cycle with ovulation, thus establishing normal fertility. As in Addison's disease, steroid replacement will need to be increased during times of stress, including labour which may be additionally complicated by cephalopelvic disproportion due to an android pelvis. Functional ovarian tumours are uncommon. Oestrogen-secreting tumours produce menorrhagia in women of reproductive age and fertility is impaired because of anovulation. Androgen-secreting tumours of the ovary are rare. Functional benign and malignant adrenal tumours secrete all adrenal hormones to a varying degree, the dominant hormone dictating the mode of presentation. Isolated androgen-secreting adenomas are rare and functional adrenal adenomas are typically discovered during the investigation of Cushing's syndrome. The presentation of an adrenal carcinoma is,

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however, often dominated by virilization. Both adrenal and ovarian tumours tend to produce a marked androgenization with clitoromegaly, male pattern of hair loss, increased musculature, mammary atrophy and deepening of the voice. As adrenal tumours are characterized by overproduction of both testosterone and testosterone precursors high levels of dehydroepiandrosterone sulphate (DHA-S) are often found in association with a high testosterone level. In contrast with ovarian tumours, DHA-S is normal. Anatomical localization of the tumour can be achieved with ultrasound, computerized tomography (CT) scanning or occasionally selective venous catheterization of the adrenal or ovarian veins. Virilizing tumours rarely affect the fetus. It is not possible to discriminate reliably between CAH and a virilizing tumour on the basis of the clinical presentation and the estimation of testosterone, androstenedione or 17-OHP levels; all cases should therefore be screened with ultrasound of the ovaries and both ultrasound and computerized tomography of the adrenals. A recent report documented the secretion of inhibin by granulosa cell ovarian tumours in patients presenting with amenorrhoea and infertility (Lappohn et al, 1989). Further study may reveal a role for inhibin in other conditions of impaired fertility. HYPOTHALAMOPITUITARY DISEASE

A deficiency of either gonadotrophin-releasing hormone (GnRH) or of the gonadotrophins (luteinizing hormone (LH), follicle-stimulating hormone (FSH)) themselves will result in delayed puberty or amenorrhoea. The deficiency may be congenital or acquired. Congenital hypogonadotropic hypogonadism may occur as an isolated defect, in combination with a deficiency of other pituitary hormones (usually growth hormone), or as part of a syndrome as in Laurence-Moon-BardetBiedl, when it is associated with polydactyly, mental retardation, obesity and retinitis pigmentosa. Any acquired pituitary pathology may give rise to a gonadotrophin deficit. Investigation will reveal no response to acute stimulation with GnRH, and no response to clomiphene. At the time of puberty, maturation of secondary sexual characteristics is achieved with a low dose of exogenous oestrogens alone and thereafter maintained by long-term oestrogen-progesterone replacement, best given in the form of the oral contraceptive. Fertility can be induced with human menopausal gonadotrophins (hMG) and human chorionic gonadotrophin (hCG) or, more physiologically, by pulsatile G n R H therapy. Congenital hypothalamic hypogonadism is rare. It occurs in Kallman's syndrome in association with anosmia, colour blindness, renal and midline facial deformities (Lieblich et al, 1982). There are multiple causes of the acquired form, but it is most commonly encountered in weight, stress or exercise-related amenorrhoea, although inflammatory, neoplastic, vascular or traumatic lesions in the hypothalamus may give rise to the same state. Investigation reveals low or normal basal levels of gonadotrophins and oestrogen deficiency. There is no response to the anti-oestrogen clomipheneo

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Chronic intermittent stimulation with GnRH will best differentiate a hypothalamic lesion from a pituitary lesion but the latter is uncommon. In congenital hypothalamic hypogonadism, puberty can be induced with pulsatile GnRH therapy (Stanhope et al, 1987), except in the rare cases of a primary anterior pituitary hormone deficiency (Lieblich et al, 1982). In practice, however, puberty is best induced by administration of exogenous oestrogens. When puberty is complete, secondary sexual characteristics are maintained with oestrogens, given as above, in the form of the oral contraceptive. Fertility can be achieved with pulsatile GnRH therapy (Crowley and McArthur, 1980) or exogenous gonadotrophins. Treatment of the acquired forms of gonadotrophin deficiency may well involve correction of the underlying disease, e.g. in weight-loss associated amenorrhoea. Prolactin-secreting pituitary adenoma

Hyperprolactinaemia is found in up to 20% of non-pregnant women with amenorrhoea (Franks et al, 1975); there are multiple causes • • • • • • • • •

prolactin-secreting pituitary adenoma hypothalamic/stalk lesion hypothyroidism drugs: dopamine antagonists dopamine depleting agents postoral contraceptive empty sella chronic renal failure idiopathic

Patients commonly present with amenorrhoea, galactorrhoea, infertility and hirsutism. Hyperprolactinaemia is due either to a disorder in the physiological control of its production and release or to a pathological autonomous proliferation of lactotrophs as is found in 40% of cases (Jacobs, 1981). The former may be divided into: (i) deficiency of inhibitors due to structural damage of the hypothalamus or disruption of the normal blood supply to the pituitary by lesions of the stalk, (ii) loss of lactotroph response to inhibitors seen during treatment with dopamine antagonists, and (iii) excess stimulation of lactotrophs, as in hypothyroidism. Practically speaking, it is necessary to exclude drug causes, hypothyroidism and renal impairment before attempting to identify a structural abnormality of the hypothalamopituitary axis. Tumours or inflammatory lesions of the hypothalamus disrupt synthesis of dopamine, the prolactin inhibitor, whilst tumours or section of the stalk disrupts the normal blood supply of the pituitary and removes dopamine inhibition of prolactin secretion. Non-functioning tumours of the pituitary may, through their size, alter the usual pattern of pituitary blood flow and give rise to 'disconnection hyperprolactinaemia'. The demonstration of a macroadenoma by CT or magnetic resonance imaging (MRI) in the presence of an elevated prolactin of greater than 6000 mU makes 'disconnection hyperprolactinaemia' unlikely and the diagnosis of a functional macroprolactinoma almost certain (Bevan et al, 1987).

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Prolactinomas are now more frequently recognized due to increases in both awareness and diagnostic sophistication. The correct management of these tumours is still uncertain, primarily due to a lack of information about their natural history. The choice lies between medical treatment with dopamine agonists, surgical resection or external irradiation. The debate is most intense in the case of microprolactinomas and management differs widely. In the presence of galactorrhoea with regular menstruation, the patient may be kept under regular review with annual or biannual CT scanning. In those with galactorrhoea and amenorrhoea the potential effects of hypo-oestrogenization indicates the need for therapy, the choice lies between bromocriptine and transsphenoidal surgery. The advantage of medical therapy lies in its ability to effectively restore regular menstruation and fertility whilst suppressing galactorrhoea without an operation. Although bromocriptine reduces the size of some prolactinomas (McGregor et al, 1979), it is not well tolerated by all patients and does not alter the underlying problem which recurs on cessation of therapy (Besser et al, 1972; Besser and Thorner, 1976). Surgery by comparison effects an initial cure in 90% of patients, although up to 40% may subsequently relapse (Serri et al, 1983). The transsphenoidal route may be complicated by cerebrospinal fluid (CSF) rhinorrhoea, pan-hypopituitarism, meningitis or diabetes insipidus. The risk of enlargement of a pituitary tumour during pregnancy is considered below. Surgery and medical treatment are probably equally as effective in the restoration of fertility and the choice of therapy is based on the consideration of the above factors, together with the availability of neurosurgical expertise and patient preference. In the management of macroprolactinomas, observation has no place due both to the endocrine consequences and to the risk of visual impairment. Surgery alone will cure a maximum of 28% of patients (Wilson and Dempsey, 1978; Dominique et al, 1980). If radiotherapy is not given then 90% will recur (Sheline, 1973), suggesting that either macroprolactinomas regrow more frequently than microprolactinomas or that complete operative removal is comparatively rare. Bromocriptine, however, effectively reduces the size of between 53 and 100% of macroprolactinomas (McGregor et al, 1979; Weiss et al, 1983). Bromocriptine preoperatively appears to increase surgical cure rate; 7 of 10 patients whose tumour had shrunk on bromocriptine achieved a surgical cure (Weiss et al, 1983). The optimum management of a macroprolactinoma may involve all three modalities of therapy. The problem of prolactinoma expansion during pregnancy has long been recognized. The normal pituitary mass increases by 10-20% during pregnancy due predominantly to lactotroph hyperplasia (Goluboff and Ezrin, 1969). The rate of occurrence of symptomatic expansion of a prolactinoma has been reported in one series as being 6% for untreated microprolactinomas, 36% for untreated macroprolactinomas and 7% in treated macroprolactinomas. Active treatment during pregnancy or in the early puerperium was necessary in 50% of symptomatic patients in the untreated macroprolactinoma group; in the other groups symptoms subsided with delivery (Gemzell and Fu Wang, 1979). In another review in which the nature of the underlying tumour was not specified, 39% of untreated[

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patients experienced symptomatic tumour expansion, 30% requiring active intervention during pregnancy, as compared with 9 % and 1% respectively in the previously treated group (Magyar and Marshall, 1978). In a later series of 70 patients with prolactinomas removed by transsphenoidal surgery, 40 subsequently became pregnant. Although 5 of 29 studied after delivery showed evidence of recurrence, none had evidence of tumour enlargement during pregnancy (Samaan et al, 1984). Overall, cases treated during pregnancy experienced an increased rate of premature labour and multiple pregnancy was more common due to hyperstimulation. Patients with microprolactinomas run a lower risk of significant tumour expansion during pregnancy. Those who desire to become pregnant may be managed with transsphenoidal adenectomy or bromocriptine and thence if necessary with GnRH to restore fertility. In the case of a macroprolactinoma, the risk of tumour expansion is substantial and treatment aimed at the removal of the tumour or reduction in its size should be instituted before conception. The form of therapy is still debated; most data would suggest that tumour bulk reduction can be achieved with bromocriptine, which can be followed by surgery or irradiation if necessary. Clearly, full pituitary replacement may be required if pituitary ablation is performed, including induction of ovulation with hMG and hCG (Gemzell, 1975). Once pregnant, patients of both groups should be kept under close review for signs of tumour expansion. If tumour expansion is suspected and confirmed by MRI, delivery will remove the stimulus to tumour growth and the tumour will spontaneously shrink. Alternatively, if delivery is not possible, bromocriptine effectively reduces the size of tumours during pregnancy (Roon et al, 1981) and has been given throughout pregnancy without complication (Canales et al, 1981; Konopka et al, 1983). If the tumour is unresponsive to bromocriptine and delivery need only be postponed for a short period, then oral steroids may induce shrinkage, both directly and by reducing oestrogen production from the fetoplacental unit. Finally, transsphenoidal adenectomy will successfully reduce tumour bulk but is associated with an increase in the rate of premature delivery (Gemzell and Fu Wang, 1979). Breast-feeding does not appear to enhance prolactinoma growth and is not contraindicated (Bergh et al, 1984). Bromocriptine will not only suppress lactation but remove prolactin inhibition of ovulation and patients should be advised to take contraceptive measures, preferably using a barrier method. Oestrogen-based contraceptive methods should probably be avoided. The origin of the amenorrhoea and hypo-oestrogenaemia found in cases of prolactinoma is obscure. A macroprolactinoma may compress gonadotrophinsecreting tissue and disrupt the normal pituitary blood supply and thus the normal flow of pulsatile GnRH to gonadotrophs. However, a microprolactinoma which neither compresses gonadotrophs nor disrupts blood flow may still cause amenorrhoea. It is suggested that an elevated prolactin may inhibit folliculogenesis either by a direct effect on the ovary (McNeilly, 1980) or indirectly by an effect on the hypothalamopituitary axis. Prolactin may render the ovary unresponsive to LH or the gonadotrophs unresponsive

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to the lack of oestrogen which, in the menopausal state, results in marked elevation of LH and FSH. However, both the gonadotrophin and the ovarian oestrogen response to G n R H are normal (Caro and Woolf, 1980) and ovulation can be restored by prolonged G n R H therapy (Leyendecker et al, 1980) suggesting that a pituitary or ovarian abnormality is unlikely. It is recognized that the pattern of LH release is a reflection of G n R H pulsation and that normal gonadotrophin secretion is critically dependent on G n R H pulse frequency and amplitude (Wildt et al, 1981). The pulsatile release of LH is found to be impaired in some patients with profiles of LH revealing two patterns, one in which LH remains undetectable and the other in which low-frequency large-amplitude pulses are observed; both are correctable with bromocriptine (Sauder et al, 1984; Klibanski et al, 1984). Inhibition of GnRH release may be the root cause of the hyperprolactinaemic hypogonadal state, induced by a direct effect of prolactin, increased dopaminergic (Quigley et al, 1979) or opioid (Lightman et al, 1981) inhibitory tone or increased adrenal androgen production. As dopamine agonists reduce prolactin and correct LH pulsatility, it is unlikely that dopamine has a role in the suppression of G n R H release, furthermore, studies in the male rat reveal that prolactin-induced gonadotrophin abnormalities occur independently of portal dopamine levels (Weber et al, 1983).

Acromegaly Women with acromegaly rarely experience menstrual irregularity early in the disease process; the problem becomes more frequent with disease progression and overall pregnancy is rare in active acromegaly (Table 1) (Jadresic et al, 1982). In 25% of cases, hyperprolactinaemia coexists, due either to cosecretion of prolactin by tumour cells or stalk compression (Franks et aI, 1976); in the remainder the menstrual disorder is due either to compression of gonadotrophs or to mild ovarian or adrenal hyperandrogenization. In a few cases, polycystic ovaries have been reported in association with acromegaly (Nagamani et al, 1980). In cases with associated hyperprolactinaemia, bromocriptine has been used successfully to restore fertility (Luboshitzky et al, 1980; Bigazzi et al, 1979). The maternal-fetal transfer of growth hormone has been reported to be negligible (King et al, 1971) and apart from reports of Table 1. Menstrual disordersin acromegaly. No. patients (>45yr) Secondary amenorrhoea Oligomenorrboea Primary amenorrhoea Mean age + SE (yr) (range) Mean growth hormone levels (mU/l) (range) Mean lateral fossaarea (ram2) (range) From Jadresic et al (1982) with permission.

Present 24/31 (77%) 14/31 (45%) 9/31 (29%) 1/31 (3%) 31 + 1.3 (20-44) 170 (38-567) 304 (97-1000)

Absent 7/31 (23%)

36 + 3.6 NS (17-44) 145 NS (21-352) 180 P = 0.03 (83-251)

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excess fetal growth (Abelove et al, 1954) and one in which mental retardation was also observed (Fisch et al, 1974), the fetus is not thought to be affected by acromegaly, nor acromegaly by pregnancy.

Sheehan's syndrome Sheehan's syndrome is the state of hypopituitarism secondary to peripartum pituitary infarction. As the pituitary gland increases in size during pregnancy, transient hypotension due either to an ante- or postpartum haemorrhage is more likely to compromise the blood supply to the pituitary and result in infarction. Sheehan's syndrome is usually recognized in the early postpartum period but may present late with secondary amenorrhoea. While no particular hierarchy of pituitary hormone loss occurs, clinically failure to lactate and mammary gland involution due to prolactin deficiency is noted first, followed by amenorrhoea and loss of axillary and pubic hair. Adrenocorticotropic hormone (ACTH) deficiency usually becomes evident next with lethargy, weakness, dizziness and anorexia and finally the absence of thyroid-stimulating hormone (TSH) may present with symptoms of hypothyroidism. The condition is managed with full replacement including cyclical oestrogens with progesterone. Fertility, if desired, is achieved by induction of ovulation with hMG and hCG. Diabetes insipidus rarely occurs as part of Sheehan's syndrome and is usually masked by the coexistent hypocortisolism.

Lymphocytic adenohypophysitis Lymphocytic adenohypophysitis is a rare condition associated with a lymphocytic infiltrate of the pituitary. It may mimic a pituitary mass and may resolve spontaneously (Meichner et al, 1987; McGrail et al, 1987). It usually occurs in the early postpartum period and its association with pituitary autoantibodies suggests that a common autoimmune mechanism may underlie both lymphocytic adenohypophysitis and postpartum thyroiditis. Pituitary antibodies were detected in the serum of 23 women of a group of 128 randomly selected women in the postpartum period; 25% of the autoantibody positive subjects went on to develop clinical signs of hypopituitarism as opposed to 4% of the antibody negative group (Engleberth and Jezkova, 1965). Clearly this condition warrants further investigation and should be considered in the differential diagnosis of a woman presenting in the postpartum period with symptoms and signs of hypopituitarism or of a pituitary mass.

ADRENAL DISEASE Cushing's syndrome Conception is rare in untreated Cushing's syndrome (Cope and Raker, 1955; Welbourn et al, 1971). In the initial stages of the disease, menstrual

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irregularities are reported in 30%, with the figure increasing to 70% in advanced disease (Iannacome et al, 1959). Pregnancy may obscure the diagnosis of Cushing's syndrome; when suspected the diagnosis should be based on the same investigations as in the non-pregnant state. If the biochemistry is suggestive then further investigation including MRI of pituitary and MRI or ultrasound of the adrenal should be undertaken. Gormley reviewed 31 cases of Cushing's syndrome in pregnancy; 23 delivered live infants, 11 prematurely. Virilization was not seen in the fetus. Of the 31 cases, 14 were due to pituitary adenoma, 12 adrenal adenoma and 5 adrenal carcinoma (Table 2) (Gormley et al, 1982). The management is dependent on the underlying cause and the stage of pregnancy. If the diagnosis is made during the first trimester then, in view of the high fetal loss and potential complications, termination should be advised to allow the institution of effective treatment. In the second trimester in the absence of virilization or MRI changes suggestive of an adrenal carcinoma, metyrapone is reported to be effective and to have no adverse effects on the fetus (Gormley et al, 1982), although removal of an adrenal adenoma has been successfully performed (Grimes et al, 1973). In the third trimester, delivery should be effected as soon as possible and treatment commenced (Van der Spuy and Jacobs, 1984a). The ability of the placenta to convert cortisol to cortisone largely protects the fetus from the adverse effects of high maternal endogenous steroids (Mitchell et al, 1981). In addition, high fetal levels of progesterone compete with cortisol for. binding sites. Little ACTH crosses the placenta (Winters et al, 1974) and the fetal adrenal is relatively insensitive to it (Mitchell et al, 1981), therefore pituitary-driven Cushing's does not affect the fetal adrenal gland. Table 2. Outcome of pregnancy in Cushing's syndrome. Aetiology

No. pregnancies

No. successful pregnancies

Pituitary dependent

14

11

preterm term

5 6

Adrenocortical adenoma

12

8

preterm term

4 4

Adrenocortical carcinoma

5

4

31

23

preterm term preterm term

2 2 11 12

Total

From Gormley et al (1982) with permission.

High levels of maternal cortisol result in suppression of adrenal DHA-S production which is the major precursor for placental production of oestriol, thus limiting the usefulness of urinary oestriol in the monitoring of the progress of pregnancy. Metyrapone too inhibits oestriol synthesis (Gormley et al, 1982). Addison's disease

When the diagnosis of Addison's disease predates conception there are

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usually no complications during pregnancy. Any stressful event will have to be covered with an increase in steroid intake. At the time of labour, increased parenteral steroids should be given and tapered to the usual maintenance regimen in the postpartum period. If, however, the onset of Addison's coincides with early pregnancy then increased pigmentation, nausea and vomiting may be taken as signs of pregnancy and the diagnosis missed with an ensuing high rate of fetal loss (Brent, 1950). Diagnosis is based on the findings of a low cortisol, high ACTH and loss of cortisol response to Synacthen. Replacement is with 30 mg hydrocortisone daily in divided doses with 100 txg of fludrocortisone once daily. Unlike autoimmune thyroid disease, there are no reports of an increased incidence of autoimmune adrenal disease in the puerperium, nor of any impact of maternal disease on the fetus.

Phaeochromocytoma Schenker's review of 112 pregnancies in 89 women with a phaeochromocytoma reported high rates of fetal (54%) and maternal (48%) mortality. Recognition and appropriate treatment reduced mortality to 50% and 17% respectively (Schenker and Chowers, 1971). Presentation, as in the nonpregnant state, is characterized by periodic episodes of paroxysmal or sustained hypertension, palpitation, severe anxiety, headache and vomiting. Peculiar to pregnancy is the greater occurrence of convulsions, visual symptoms and an increase in the frequency of attacks experienced whilst supine, presumably related to pressure of the gravid uterus on the tumour. Maternal death was due to cerebrovascular accident, pulmonary oedema, shock, cardiac dysrrhythmia or disseminated malignancy, whilst that of the fetus to increased spontaneous abortion and perinatal mortality (Schenker and Chowers, 1971). Tumour localization is usually achieved with MRI scanning with or without venous sampling and arteriography. During pregnancy, invasive procedures carry an increased risk, ultrasound is therefore the initial imaging method of choice. Monoiodobenzguanine scanning is contraindicated in pregnancy as the radio-active iodine may cause fetal thyroid ablation. Tumour distribution is usually: 50% in the right adrenal, 29% in the left adrenal, 10% bilateral and 10% extra-adrenal (purely noradrenaline secreting) (Schenker and Chowers, 1971). Management is initially medical using the alpha-blocker phentolamine (Fudge et al, 1980; Griffith et al, 1974). Beta-blockers are not without risk to mother and fetus (Tunstall, 1969; Gladstone et al, 1975) and should be used only in the presence of dysrrhythmias or tachycardia. An acute hypertensive crisis should be managed with phentolamine and or sodium nitroprusside. Operative intervention is dependent on the stage of pregnancy; in the first or second trimester of pregnancy the tumour should be removed and the risk of associated abortion explained in context. In the third trimester, caesarian section should be combined with adrenalectomy (Van der Spuy and Jacobs, 1984). The success of the procedure is dependent on meticulous anaesthetic preparation (Griffith et al, 1974). In the postoperative period, hypotension

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will usually respond to intravenous fluids; rarely a noradrenaline infusion is required. The placental transfer of catecholamines is limited and the fetus largely protected from elevated maternal levels (Sodha et al, 1984). PARATHYROID DISEASE

Maternal calcium loss increases during pregnancy. Whilst parathyroid hormone levels are not elevated in either mother or fetus, both vitamin D and calcitonin levels are. In the fetus, calcitonin may be elevated in response to high levels of circulating calcium, and in the mother perhaps to protect the skeleton from the increased calcium demands of pregnancy, which are met predominantly by increased intestinal calcium absorption secondary to the elevated vitamin D levels. Active transport of calcium by the placenta, which is dependent on the fetal equivalent of parathyroid hormone, maintains the concentration gradient between the fetal and maternal circulations (Fisher, 1986). Primary hyperparathyroidism is said to have no effect on fertility, but is underrepresented in pregnant women, implying that either fertility is decreased or that the increased calcium demands of pregnancy serve to mask milder cases of hyperparathyroidism (Montoro and Mestman, 1981; Johnstone et al, 1972). The commonest cause of primary hyperparathyroidism is an adenoma (80%), followed by hyperplasia (15%). The remainder is made up of cases associated with multiple endocrine neoplasia and carcinoma (5%). During pregnancy, hyperparathyroidism may present as a random finding of an elevated calcium, neonatal tetany or with the typical symptoms and signs of hypercalcaemia. Undiagnosed hyperparathyroidism increases rates of abortion; intrauterine death and premature labour and causes neonatal tetany (Table 3) (Deutsch et al, 1980). The basis of the emergency management of hypercalcaemia in pregnancy is identical to the non-pregnant state. Deutsch recommended surgical intervention, preferably during the second trimester, in the management of these patients and reported a marked improvement in rates of fetal survival (Deutsch et al, 1980). Table 3. Outcome of pregnancy with maternal hyperparathyroidism. Parathyroidectomy in pregnancy

No. women

No. pregnancies

Normal birth

Fetal/neonatal complications

During After

10 33

10 52

8 21

2 31

Total

43

62

29

33

From Deutsch et al (1980) with permission.

Hypoparathyroidism complicates between 0.2 and 3.5% of thyroidectomies, the remaining cases are associated with autoimmune disease (Van der Spuy and Jacobs, 1984b). Hypocalcaemia presents with clumsiness,

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tetany, paraesthesiae, stiffness and laryngeal spasm causing stridor. With no treatment there is a high fetal and maternal mortality. In the acute state, intravenous calcium gluconate should be administered, initially as a bolus and then as an infusion, followed by oral vitamin D and calcium supplements. In all cases, serum magnesium should be checked. Cases of hypoparathyroidism diagnosed before pregnancy should have regular estimation of serum calcium and, in the immediate postnatal period, supplements may occasionally need to be stopped as calcium levels have been reported to rise markedly (Wright et al, 1969). Rarely, in cases of unrecognized or undertreated hypoparathyroidism, the resultant fetal hypocalcaemia induces a state of congenital hyperparathyroidism with osteitis fibrosa and osteoporosis. Perinatal mortality is also increased. The skeletal changes usually resolve in the first year of life (Landing and Kamoshita, 1970). THYROID DISEASE

Both hypo- and hyperthyroidism are associated with impaired fertility and when unrecognized during pregnancy, with increased fetal mortality and morbidity. The behaviour of autoimmune thyroid disease (AITD) during pregnancy reflects the pregnancy-induced suppression of the immune system, with the characteristic amelioration during pregnancy and exacerbation in the postpartum period. The clinical picture is matched by changes in both total IgG and thyroid-specific IgG levels (Zakarija and MacKenzie, 1983; Fung et al, 1988). Goitre is particularly common in women not only because women are more prone to AITD, but also because increased renal loss of iodide results in a mild iodine deficiency state, which sensitizes the gland to the growthpromoting properties of thyroid-stimulating hormone (TSH) (Bray, 1968). The degree of iodine deficiency is usually insufficient to induce frank hypothyroidism, but may induce goitre formation during puberty and pregnancy, both times of increased iodine demand. During pregnancy, renal loss of iodide increases three-fold (Aboul-Khair et al, 1964) and the growthstimulating properties of TSH may be augmented by placental thyrotropic factors. Oestrogens increase thyroid-binding globulin (TBG) production with a concomitant rise in total T3 and T4 levels. A state of compensated hypothyroidism is thought to exist during pregnancy with levels of free hormones falling and TSH rising though all remain within the normal range (Fung et al, 1988). The fetal thyroid matures through three stages; in the first 72 days colloid is not identifiable, between 72 and 80 days colloid becomes evident, and beyond 80 days when follicles are present the thyroid is capable of producing thyroid hormones. Before 12 weeks, therefore, the fetus is almost certainly dependent on the placental transfer of maternal thyroid hormone for normal development and in the absence of functioning fetal thyroid tissue, as in thyroid agenesis, dyshormonogenesis or over-treatment of maternal hyperthyroidism, the fetus is dependent on maternal thyroxine to term (Larsen, 1989; Vulsma et al, 1989).

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Hypothyroidism Hypothyroidism is characterized by menorrhagia, but occasionally prolonged periods of amenorrhoea and anovulation occur. Hypothyroid patients have reduced levels of sex hormone-binding globulin (SHBG) (Anderson, 1974) and concomitantly reduced testosterone and oestrogens (Akande, 1975); with anovulatory cycles LH and FSH are also reduced. These changes are independent of hyperprolactinaemia, which occasionally occurs in hypothyroidism. Thyroid hormone replacement reverses these changes and restores fertility. Pregnancy does occur in hypothyroidism (Montoro et al, 1981), but there are increased rates of recurrent abortion. Hypothyroidism may be a result of Hashimoto's thyroiditis, primary myxoedema, Graves's disease (due to over-treatment), or iodine deficiency. Hypothyroidism in the first trimester impairs fetal neurological development, causing deafness, spasticity and low IO. After the first trimester the fetus is capable of synthesizing its own thyroid hormones and therefore, with maternal deficiency, more marked signs of neonatal hypothyroidism are only evident if fetal thyroid hormone synthesis is inhibited, either by continuing iodine deficiency, goitrogen ingestion, thyroid agenesis or thyroid dyshormonogenesis. A cretin typically appears sluggish, feeds poorly, has a hoarse cry, is constipated, has coarse dry skin, a large tongue, persisting umbilical hernia and prolonged neonatal jaundice (Rodin and Rodin, 1989). With maternal hypothyroidism it is essential, particularly in the first trimester, to optimize thyroid replacement; doses typically range from 100 to 200 txg and TSH values should be checked regularly. In areas of severe iodine deficiency two clinical syndromes are recognized in affected children, both have the neurological features of cretinism but some have goitres and appear clinically euthyroid, the other group have atrophied thyroids and are clinically hypothyroid with features of myxoedema, dwarfism and sexual infantilism. In the serum of the latter group antibodies that inhibit the growth of thyroid cells in vitro have been identified and are thought to cause the observed thyroid atrophy. The precipitant, as in other autoimmune diseases, is unknown (Boyages et al, 1989).

Hyperthyroidism In the non-pregnant state severe hyperthyroidism is characterized by amenorrhoea, perhaps induced by weight loss, but with relatively elevated LH and FSH during the cycle and loss of the mid-cycle gonadotrophin peaks with consequent anovulation and low progesterone levels (Akande and Hockaday, 1975). Circulating oestrogens are increased (Akande and Hockaday, 1975), as is SHBG (Anderson, 1974) and testosterone (Ridgeway et al, 1982). It is postulated that the high SHBG reduces free oestradiol and therefore both negative and positive feedback at the relevant stages of the menstrual cycle, resulting in anovulation and amenorrhoea (Akande and Anderson, 1975). In less severe disease, cycles are typically ovulatory but associated with hypomenorrhoea, which may be a direct effect of T3 on endometrial development as T3 receptors have been found in the rat uterus (Evans et al, 1983).

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Thyrotoxicosis is diagnosed in between i in 500 and 1 in 1500 pregnancies and is due to Graves's disease in 95% of cases. Both pregnancy and thyrotoxicosis may present with goitre, heat intolerance, palpitations, vomiting, sweating or tiredness hence the condition may not be obvious. Diagnosis is based on the demonstration of elevated free thyroid hormones in the presence of a suppressed TSH. The risk to the fetus is not derived from the increased free thyroid hormones, but from: (i) the effect of the mother's disease and therefore the passage of thyroid-stimulating immunoglobulins (TSI) or TSH receptor binding inhibiting immunoglobulins (TBII) across the placenta which may render the fetus thyrotoxic or hypothyroid respectively (Zakarija and MacKenzie, 1983), and (ii) treatment of the maternal disease. The use of radio-iodine is contraindicated during pregnancy. Treatment is usually based on the use of either carbimazole or propylthiouracil. Propranolol has been advocated to suppress the peripheral manifestations of thyrotoxicosis if they are severe, before surgery or pending diagnosis and the institution of antithyroid therapy (Langer et al, 1974); however, its routine use is not recommended due to reports of adverse effects on intrauterine growth, uterine function (Rubin, 1981) and the newborn (Gladstone et al, 1975). The use of iodide or over-treatment with an antithyroid drug may stimulate the development of a large fetal goitre causing neck extension, a brow presentation and cephalopelvic disproportion (Komins et al, 1975). Either propylthiouracil or carbimazole may be used, the advantages of propylthiouracil are its ability to inhibit peripheral conversion of T4 to T3 and less risk of inducing blood dyscrasias. Both drugs, however, cross the placenta and risk inducing hypothyroidism in the fetus and neonate. The use of the smallest dose necessary to control maternal disease minimizes the risk. There is no place for the 'block and replace' method of treatment due to the differential passage of antithyroid agents and thyroid hormones across the placenta. It is suggested that if thyrotoxicosis is not controlled by 20mg of carbimazole or 300mg of propylthiouracil per day or with allergic reactions to antithyroid treatment, then surgery should be considered; optimally late in the second trimester. In preparation for surgery the dosage of antithyroid treatment should be increased. Minimal amounts of antithyroid drugs are found in breast milk; breast-feeding is not therefore contraindicated. In a series of 33 cases of severe hyperemesis gravidarum 73% were found to have increased free T4 levels. All returned to normal in a period of several weeks, independent of the treatment used. The birth weight of the children born to mothers with elevated free T4 levels was consistently reduced, but no evidence of neonatal hyperthyroidism was recorded (Bouillon et al, 1982). In the absence of Graves's disease, the presence of thyrotoxicosis implies the existence of a pregnancy-related thyrotropic factor or factors, possibly hCG which may also be involved in the occurrence of hyperemesis gravidarum. Those cases of elevated free T4 due to TSI run the risk of both intrauterine (Serup and Petersen, 1979; Check et al, 1981) and neonatal thyrotoxicosis (Zakarija and MacKenzie, 1983). Immunological studies help to identify those at risk.

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The management of hyperthyroidism occurring during pregnancy should be based on the clinical severity and the degree of derangement of biochemical parameters, of which TSH and free T4 seem to be the most accurate (Bouillon et al, 1982).

Postpartum thyroid dysfunction The postpartum period often sees an exacerbation of autoimmune conditions; levels of autoantibodies rise and clinical and biochemical evidence of active disease becomes apparent (Fung et al, 1988). Postpartum thyroid dysfunction (PPTD) may represent the activation of a previously subclinical autoimmune thyroiditis; a Swedish series reported an incidence of 6.5% (Jansson, 1984) and a Japanese of 5.5% (Amino et al, 1982). In the Swedish report, in all cases either thyroid microsomal antibodies (TMA) were positive or thyroid biopsy revealed a lymphocytic infiltrate and the greater the titre of TMA the greater the chance of PPTD (Jansson, 1984). These findings are in contrast to those of Fung et al who reported that TMA titres were less strongly predictive of the occurrence of PPTD (Fung et al, 1988). Two forms of postpartum thyrotoxicosis are recognized, one destructive (as in De Quervain's thyroiditis) with a low radio-active iodine uptake (RIU), the other due to TSI as in Graves's disease with a high RIU. In a report from Japan of a series of 41 pregnancies in 35 women with Graves's disease in remission, 78% developed thyrotoxicosis in the first 4 months postpartum. The cases were almost evenly divided between those with persistent thyrotoxicosis with high RIU, those with transient thyrotoxicosis with a high RIU, and those with destructive thyrotoxicosis with a low RIU. The last group had high titres of TMA and there was no method of distinguishing between the other two groups of thyrotoxic patients (Tachi et al, 1988). In the same Japanese series, human leukocyte antigen (HLA) associations were studied in postpartum hypothyroidism. The risk of permanent hypothyroidism was greatest with H L A DRW9 and or B51 in association with high TMA titres; long-term follow-up of all cases of postpartum hypothyroidism was recommended (Tachi et al, 1988). Treatment of PPTD is dictated by the severity of symptoms and, if instituted, requires withdrawal of treatment at intervals to assess possible recovery.

Neonatal thyroid disease Cases of intrauterine thyrotoxicosis have been reported and treatment with propylthiouracil advocated (Serup and Petersen, 1979; Check et al, 1981). In the presence of maternal autoimmune thyroid disease the transplacental passage of maternal IgG exposes the fetus to the risk of transient neonatal thyroid dysfunction. The nature of the condition is dependent on the type and titre of immunoglobulin present in the maternal circulation (Matsuura et al, 1980; Zakarija et al, 1983); and its duration on the persistence of the antibody in sufficient titre. The risk persists for the progeny of mothers with treated Graves's disease or Hashimoto's thyroiditis who may still possess TSI or TBII (Serup and Petersen, 1979; Matsuura et al, 1980). The risk of

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occurrence of neonatal thyrotoxicosis can be estimated from the measurement of antibody activity (Zakarija and MacKenzie, 1983). Neonatal thyrotoxicosis is said to carry a high mortality. Iodide, propranolol and recently sodium ipodate have been advocated as useful treatments (Karpman et al, 1987). Neonatal thyroid dysfunction is self-limiting tending to last about 6-8 weeks. Trophoblastic disease Placental extracts from normal pregnancies have been known to stimulate the thyroid for some time; the isolated factor was termed human chorionic thyrotropin (HCT) (Hershman and Starnes, 1971). HCT was eventually shown to be H C G (Kenimer et al, 1975) and a close correlation found between levels of H C G and T4 levels in cases of hyperthyroidism associated with trophoblastic disease (Nisula and Taliadouros, 1980). Treatment of the underlying pathology controls the hyperthyroidism associated with trophoblastic disease. CONCLUSION In this chapter we have considered how an endocrine disease may impair an individual's ability to both conceive and be delivered of a healthy full-term infant. There are few endocrine conditions that result in an irreversible loss of fertility that is usually restored with correction of the primary disorder. Pregnancy may mimic or alter the clinical presentation of several endocrine diseases and its effect on the biochemical parameters routinely used to assess endocrine function can make the diagnosis of an endocrine disorder extremely difficult. However, failure to make a diagnosis or the incorrect management of an endocrine disease once diagnosed may have severe consequences in terms of fetal and maternal prognosis. Recent advances in the understanding of placental transfer of thyroid hormones have emphasized the importance of maintaining the maternal euthyroid state during pregnancy and clarified some aspects of neonatal thyroid function. Future research will reveal the obscure origins of the polycystic ovary syndrome, deepen our understanding of and ability to treat autoimmune conditions and establish the correct management of hyperprolactinaemic patients. The importance of pregnancy-induced changes in the endocrine system and the vast array of factors and hormones produced by the fetoplacental unit remain to be elucidated. Increased understanding of these aspects of pregnancy will lead not only to an improvement in the management of pregnancy-associated endocrine disease but may also suggest new areas of therapeutic potential. REFERENCES Abelove WA, Rupp JJ & Paschkis KE (1954) Acromegaly and pregnancy. Journal of Clinical Endocrinology and Metabolism 14: 32-44.

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