JOURNAL DISCUSSION Impaired fertility caused by endocrine dysfunction in women

1
JOURNAL DISCUSSIONImpaired fertility caused by
endocrine dysfunction in women

• ??? ?? ??
• Brinda N. Kalro
• Endocrinol Metab Clin N Am
• 32 (2003) 573-592

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Introduction

• Fertility in women is tightly regulated by the
  hypothalamo-pituitary-ovarian (HPO) axis
• Endocrine dysfunction of the thyroid, pancreas,
  adrenal, and pituitary frequently disrupts the
  HPO axis and adversely influences overall
  fecundity
• Between 10 and 23 of repetitive pregnancy
  losses are attributed to endocrine dysfunction

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Thyroid disorders

• Reproductive disorders ranging from abnormal
  sexual development to menstrual irregularities
  and infertility have been associated with thyroid
  disorders
• Routine screening revealed that 5.1 of the
  infertile population had abnormal thyroid
  function tests
• Pregnancy in women with overt thyroid disease is
  uncommon, but can be fraught with complications
  and have grave consequences when it does occur
• Evaluation of the thyroid axis in women
  presenting with fertility problems is imperative

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Hyperthyroidism

• Oligomenorrhea most common menstrual disorder
  (58 of women with hyperthyroidism) and may
  progress to amenorrhea (5)
• Polymenorrhea less frequent (5)
• Menstrual irregularities sometimes precede overt
  thyroid dysfunction
• Severe hyperthyroidism ? ?LH FSH, loss of
  midcycle LH peak ? anovulation, low progesterone
• Thyroid hormone ? ?SHBG and total estrogen and
  testosterone, but ?free fraction

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Hyperthyroidism

• Increased thyroid hormones in maternal
  circulation do not increase the risk to the fetus
  per se
• But transplacental passage of thyroid-stimulating
  Ig, thyroid receptor antibodies, or antithyroid
  drugs may result in hypothyroid or thyrotoxic
  fetus
• Subclinical or mild hyperthyroidism is often not
  associated with subfertility and anovulation
• Maternal and fetal morbidity is increased when a
  thyrotoxic woman conceives
• The risk of pre-eclampsia, fetal loss, and
  intrauterine growth restriction is increased

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Hyperthyroidism

• Restoration of euthyroid state results in
  resumption of regular ovulatory menstrual cycles
  and fertility
• Radioactive iodine treatment is contraindicated
  in women contemplating pregnancy immediately
• Hyperthyroidism can be treated with carbimazole,
  methimazole, or propylthiouracil, but they cross
  the placenta with a potential risk of inducing
  fetal hypothyroidism
• When pharmacotherapy has not been effective or
  significantly large doses of medication are
  required, surgery should be considered

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Hypothyroidism

• Often causes polymenorrhea and oligomenorrhea,
  occasionally anovulation, and rarely amenorrhea
• Menstrual abnormality 68.2 of women with
  hypothyroidism vs. 12.2 of healthy controls
• Subclinical and frank hypothyroidism can present
  with metrorrhagia or menorrhagia usually
  resolves with thyroid replacement in 3-6 months
• Patients with hypothyroidism have reduced levels
  of SHBG and circulating estrogens and
  testosterone
• With anovulatory cycles, LH and FSH may also be
  reduced

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Hypothyroidism

• Hypothyroidism can cause a von Willebrandlike
  bleeding disorder and other defects in hemostasis
• Hypothyroidism alters steroid metabolism and
  clearance ? endometrial dysfunction
• Hypothyroidism ? ?TSH and prolactin ?
  galactorrhea (1-3 of untreated hypothyroidism),
  ovulatory dysfunction
• Subclinical hypothyroidism have been associated
  with luteal phase insufficiency
• Incidence 11.3 in women with ovulatory
  dysfunction, 3.8 in infertile women with
  ovulatory cycles

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Hypothyroidism

• Pregnancy is rare in frank hypothyroidism but can
  occur, and is associated with spontaneous
  abortions, stillbirths, prematurity, congenital
  malformations, and neurologic dysfunction
• Thyroid hormone replacement in hypothyroid women
  with previous bad outcomes significantly improves
  the outcome in subsequent pregnancies
• The developing fetus relies on maternal
  contribution of thyroid hormones hypothyroidism
  in 1st trimester ? ?fetal neuropsychologic
  development, low IQ, deafness, spasticity

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Antithyroid antibodies

• Prevalence of antithyroid antibodies
• Healthy pregnant women 15 to 20
• Women with recurrent miscarriages 20 to 25
• Women undergoing in vitro fertilization 20
• Some studies demonstrated an association between
  ATAs and spontaneous abortion
• Thyroid antibodies may coexist with other
  non-organ-specific autoantibodies, suggesting an
  underlying immunoregulatory defect, which may
  result in pregnancy loss
• ATAs also ?risk for premature ovarian failure

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Antithyroid antibodies

• Activated T cells in the endometria of women with
  ATD may secrete cytokines that adversely affect
  pregnancy outcome and possibly impair
  implantation
• Higher prevalence of ATAs was found in euthyroid
  women who failed to conceive despite multiple
  attempts at IVF and embryo transfer. But it is
  debatable that women with higher levels of ATAs
  have a poorer reproductive outcome. Routine
  assessment of ATA is therefore not currently
  recommended in euthyroid women undergoing IVF

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Acromegaly

• Approx. 25 to 30 of pituitary adenomas are
  GH-secreting tumors 20 to 25 of these adenomas
  also secrete prolactin, ACTH, or TSH
• Approx. 25 to 40 of patients with untreated
  acromegaly have hyperprolactinemia resulting in
  galactorrhea, amenorrhea, and decreased libido
• Amenorrhea can also occur in the presence of
  normal prolactin levels
• Nearly 75 of acromegalic women have menstrual
  irregularities

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Acromegaly

• Ovarian dysfunction and loss of fertility is
  consequent to pituitary mass effect, which
  results in impaired gonadotropin secretion
• Possibly also secondary to coexisting ovarian
  hyperthecosis caused by insulin resistance
• Normal fetal birth weights and fetal macrosomia
  have been described
• Fetal macrosomia may be secondary to maternal
  carbohydrate intolerance rather than from direct
  effects of maternal GH, because maternal-fetal
  transfer of GH is negligible

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Acromegaly

• There seems to be no increase in fetal mortality
  and morbidity in nondiabetic acromegalic mothers
• Pituitary GH are suppressed during pregnancy and
  return to normal a few weeks after delivery
• IGF-1, although a better indicator of disease
  activity, is often increased in pregnancy,
  therefore unreliable in the diagnosis of
  acromegaly in pregnant women
• Spontaneous pregnancy is rare in women with
  untreated acromegaly but a few pregnancies have
  been reported

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Acromegaly

• Colao observed 10 pregnancies in 6 women with
  acromegaly
• One spontaneously aborted
• Acromegaly was diagnosed in four women during
  pregnancy, all of whom delivered healthy infants
  vaginally
• Three women conceived following surgery, two of
  these had persistent, mildly elevated GH and
  IGF-1 levels
• Two women conceived during octreotide treatment.
  One remained on octreotide and delivered an
  infant with a normal birth weight. The other
  discontinued medication and delivered an
  overweight infant
• None exhibited tumor enlargement during pregnancy

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Acromegaly

• Bigazzi reported a patient maintained on
  bromocriptine during of her pregnancy
• Bromocriptine appeared to be effective in
  preventing enlargement of a GH-secreting adenoma
• Fetal development was normal
• GH levels in the infant were normal
• Prolactin levels in the fetus, however, were
  suppressed, suggesting that bromocriptine does
  cross the placenta
• Transplacental transfer of octreotide has been
  demonstrated. Half-life is prolonged 4 in the
  fetus but, to date, no adverse effects have been
  noted in infants exposed to octreotide during
  pregnancy

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Diabetes

• Insulin therapy in diabetic women successfully
  restored menstruation and fertility, and
  significantly decreased maternal mortality rates,
  although perinatal mortality rates remained high
• DM women have a higher incidence of secondary
  hypogonadotropic amenorrhea, more so if BMI is
  low and HbA1c is higher than normal
• Onset of IDDM before age of menarche is more
  likely to be associated with delayed menarche and
  menstrual irregularities thereafter

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Diabetes

• Amenorrhea and oligomenorrhea are 3 more common
  in diabetic individuals 30 of women who have
  IDDM also have menstrual irregularities
• Possible causes ?GnRH drive because of the
  stress of diabetes, altered pituitary secretion
  of LH, or an abnormal response of LH to GnRH
• Significant inverse correlation was observed
  between serum glucose levels and magnitude of LH
  response to LHRH
• Basal FSH levels tended to be lower and response
  to exogenous LHRH was also blunted

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Diabetes

• Women with IDDM and secondary amenorrhea had
  lower basal pituitary gonadotropins and estradiol
  when compared with eumenorrheic IDDM women
• Amenorrheic women also had elevated basal
  cortisol levels with blunted ACTH response to CRH
  when compared with eumenorrheic diabetic
  controls, suggesting chronic stress from IDDM
• Insulin deficiency and uncontrolled DM can also
  have detrimental consequences on folliculogenesis
  and preimplantation embryo development

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Diabetes

• Adequate glycemic control before conception is
  critical to reduce the risk of spontaneous
  abortion, fetal abnormalities, macrosomia, etc.
• Major malformations were 2 to 3 higher in
  infants of IDDM mothers, despite good glycemic
  control
• Maternal DM during early pregnancy has been
  associated with mild early fetal growth
  restriction and may be a marker for congenital
  malformations
• Women who have IDDM are at risk for magnesium
  deficiency because of increased renal loss, which
  may be a causative factor in early pregnancy loss

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Congenital adrenal hyperplasia

• 21-Hydroxylase deficiency is the most common type
  (90 of cases), followed by 11ß-hydroxylase and
  3ß-hydroxysteroid dehydrogenase deficiency
• Amenorrhea and infertility in women with CAH have
  been attributed to to adrenal hyperandrogenism,
  and more recently, to endometrial effects of
  elevated of progestagenic steroids of adrenal
  origin
• Reduced fertility rates also have been attributed
  to sexual dysfunction, nonsuppressible
  progesterone levels, failure to respond to normal
  ovulation stimulation, severity of anatomic
  defects

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Congenital adrenal hyperplasia

• Women with milder forms of 21-hydroxylase
  deficiency resume having normal ovulatory cycles
  with adequate cortisol replacement and are able
  to conceive spontaneously
• In more severe forms, however, fertility and
  childbirth rates are compromised despite
  treatment
• Decreased sexual drive and libido caused by
  elevated progesterone levels
• Elevated glucocorticoid levels in treated women
• Persistent androgen excess may predispose to
  first-trimester miscarriages

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Adrenal insufficiency

• Adrenal androgen deficiency in women ? loss of
  axillary and pubic hair, ?libido
• Approx. 25 of women with Addison's disease are
  amenorrheic secondary to chronic illness, weight
  loss, or autoimmune premature ovarian failure
  (7)
• Decreased libido and potency and amenorrhea can
  be present in both primary and secondary adrenal
  insufficiency
• Modest hyperprolactinemia may also be present

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Adrenal insufficiency

• Pregnancy in women with untreated adrenal
  insufficiency is rare
• Before the advent of glucocorticoid therapy,
  maternal mortality rates were as high as 45
• Treatment replace both mineralocorticoids and
  corticosteroids with additional doses during
  labor and delivery, surgery, or illness
• Fetal growth may be suboptimal if the diagnosis
  is confirmed late in pregnancy
• Adrenal antibodies cross the placenta but do not
  seem to adversely affect fetal adrenal function

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Cushings syndrome

• Cortisol and androgen excess ? menstrual
  abnormalities, hirsutism, acne, back pain,
  ?libido
• Approx. 70 to 85 of premenopausal women with
  Cushing's have amenorrhea and oligomenorrhea
• Pregnancy rarely occurs because of ovulatory
  dysfunction and difficulty conceiving
• Pregnancy, if occurs, is fraught with
  complications hypertension, GDM, CHF,
  hypokalemia, myopathy, emotional lability,
  spontaneous abortion, IUGR, and preterm
  delivery,?fetal morbidity and mortality
• Maternal death 4, perinatal death 15.4

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Cushings syndrome

• Hypercortisolism and hyperandrogenemia suppress
  gonadotropin secretion with impaired LH response
  to GnRH. LH levels improve following treatment
  and normalization of cortisol levels
• May also be associated with hyperprolactinemia
• Diagnostic difficulty in pregnancy
• Symptoms of hypercortisolism such as edema,
  striae, HTN, and DM can also occur in pregnancy
• Physiologic alteration in adrenocorticosteroid
  metabolism
• Dexamethasone suppressibility of cortisol
  decreases as pregnancy advances

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Cushings syndrome

• Treatment improves maternal perinatal outcome
• Surgery is recommended for Cushing's disease or
  adrenal tumors
• Metyrapone and aminoglutethamide inhibit
  steroidogenesis, with possible teratogenic
  effects. Transplacental passage could alter
  normal fetal adrenal steroidogenesis
• Ketoconazole is teratogenic and embryotoxic
• Antiprogestins, which can be used to treat
  Cushing's syndrome, are contraindicated in
  pregnancy