PITUITARY GLAND: DEVELOPMENT, NORMAL APPEARANCES, AND MAGNETIC RESONANCE IMAGING

Origin of the Pituitary Gland

T

raditional embryology states that the anterior lobe of the pituitary gland derives from an evagination (Rathke pouch) of the rostral stomodeum anterior to the buccopharyngeal membrane and the infundibulum/posterior lobe from a ventral caudal extension of the diencephalon. It is believed that contact between these 2 components is necessary and that it provides critical signaling for proliferation and determination of pituitary cell types later (Amar et al., 2003) this process seems to be regulated by the LIM homeobox genes. Although both components are derived from ectodermic germ cells, these cells express different phenotypes and histology. Those from Rathke pouch give rise to a ductless (exocrine) gland which integrates with posterior neurohypophysis at around the second month of life. The latter arises as a diverticulum of the third ventricle, which extends down (the infundibular stem) and terminates in a zone of expansion (infundibular process). Rathke pouch migrates rostrally via a canal in the body of the sphenoid bone (craniopharyngeal or basipharyngeal canal (Elsetr et al., 1993). this canal regresses (at approximately the sixth month of life) by virtue of expansion of the sphenoidal mesenchyme. Remnants of this canal may persist, and occasionally, glandular tissues may be found in those remnants (which explain the presence of sphenoidal adenomas or of functioning gland in the craniopharyngeal canal). It should be noted that some authors believe that Rathke pouch is not connected to the stomodeum, but that it represents an isolated vesicle. Others believe that the anterior lobe is actually of neuroectodermal origin, because some of its cells are capable of amine precursor uptake and carboxylation. At this time, the pars distalis enlarges and becomes the anterior lobe (Porter et al., 1977) The pars distalis extends superiorly along the anterior aspect of the infundibulum (eventually extending completely around it) as does the pars tuberalis. Thus, the pituitary stalk has components of both the anterior and posterior lobes (which explains the presence of adenomas arising in the stalk). Mesenchymal cells fill gaps found in the posterior aspect of the pars distalis (known as the fossa of Atwell), and they will eventually give raise to the gland’s portal vascular system (Amar et al., 2003). Adjacent to these cells, there is an area in the dorsal surface of the pars distalis that experiences lesser cell proliferation and becomes the intermediate lobe (pars). The pituitary fissure is a small potential space located between the anterior and the intermediate lobes, and this completes the formation of the adenohypophysis. Around the fourth month of life, the different cell populations arrange themselves around blood vessels in specific, bilateral, and nearly symmetrical groups. Acidophilic cells (prolactin releasing) are found in the lateral aspects of the anterior lobe; growth hormoneYreleasing cells are found in its anterior-lateral aspects, and adrenocorticotropic, follicle-stimulating, and thyroid-stimulating hormones are found in the lobe’s central aspect. It is possible, however, that a single cell type may be able to secrete more than one type of hormone (Aron et al., 1997) The adenohypophysis becomes functional between the first and second trimesters, whereas the activity of the neurohypophysis begins close to the time of birth. The infundibular process enlarges and contains neuroglial cells (pituicytes) and becomes the posterior lobe (pars nervosa). Nerve fibers from the hypothalamus also terminate in the neurohypophysis. Initially, the infundibular stem is hollow because of an inferior extension of the third ventricle. Eventually, its lumen is obliterated (but may persist even in adults), and all that is left behind is a depression in the anterior floor of the third ventricle, called the infundibular recess.

Medication review for pregnancy:

Medication review for pregnancy:

·        Emphasize folic acid supplements;

·        Stop (DFX) and vitamin C;

·        Stop angiotensin-converting enzyme inhibitors;

·        Change oral hypoglycemic agents to insulin;

·        Stop biphosphonates;

·        Give calcium and vitamin D supplements.

Pregnancy care:

·        Monitor cardiac function closely;

·        Increase frequency of transfusion;

·        Maintain pretransfusion hemoglobin level above 10 g/dl;

·        Carry out serial ultrasound scans to monitor fetal growth;

·        Encourage breast feeding (unless HIV positive);

·        Resume parenteral chelation after delivery;

·        Give contraceptive advice or restart estrogen replacement;

·        Resume biphosphonates after breast feeding is finished; (Suzan, 2005).

Risks associated with pregnancy:

All patients should be made aware that pregnancy per se does not alter the natural history of thalassemia. If pregnancy is managed in a multidisciplinary setting, the foetal outcome is usually favourable with a slight increase in the incidence of growth restriction. It has been shown that the risk of pregnancy-specific complications such as ante-partum haemorrhage and pre-eclampsia in thalassemia are similar to the background population. It has also been shown that DFO is not required during pregnancy in patients that are not iron overloaded and that have adequate cardiac function prior to pregnancy. Serum ferritin is likely to alter by 10℅ despite increase in frequency of blood transfusion. The aim during pregnancy is to maintain pre-transfusion haemoglobin concentration above 10g/dl (Aessopos et al., 1999).

High rate of gestational and other complications have been reported; these include intrauterine fetal-growth retardation and preterm labour, attributed to low hemoglobin levels of the mothers during gestation, which lead to fetal hypoxia (Ansari et al., 2006).

Pregnancy and Fertility in Thalassemia Major

Pregnancy and Fertility in Thalassemia Major

Despite major advance in the understanding of and treatment for individuals with transfusion-dependent β-thalassemia, pregnancies and fatherhood for those involved or affected are still relatively uncommon.

Apart from hypogonadotropic hypogonadism, the other endocrine disorders particularly relevant to fertility and pregnancy, namely, diabetes and hypothyrodism, seem to be problems that are amenable to relatively standard care, and they are not a significant bar to pregnancy in the context of thalassemia (Suzan, 2005).

Spontaneous pregnancy without hormonal assistance is reported (Skordis et al., 2004). Although the fetal outcomes for pregnancies achieved by thalassemic parents are remarkably successful, there are at least three important associated factors that must be seriously considered before encouraging a thalassemic woman to embark on pregnancy. These are cardiac impairment, liver dysfunction and the vertical transmission of viruses. Thalassemia itself seems to have no specific influence on the general well-being of pregnancy, and the only specific obstetric complication is the relatively high frequency of cesarean section (Suzan, 2005).

Although delayed onset of menarche, amenorrhea, anovulation, and infertility are relatively common in women with thalassemia major, the use of intensive transfusion regimens and careful iron chelation, together with appropriate use of ovulation induction therapy, have made pregnancy a practical possibility (Suzan, 2005).

Pregnancy checks up in thalassemia major:

·        Assess cardiac function;

·        Check liver functions;

·        Check status of viral infection;

·        Optimize diabetic control;

·        Optimize thyroid replacement;

·        Review medication;

·        Ascertain hemoglobinopathy status of male partners;

·        Determine red cell antibodies;

·        Provide Rubella immunity;

·        Optimize life style issues (e.g., smoking cessation).

Gonadal Dysfunction in Thalassemia 2

Gonadal Dysfunction in Thalassemia 2

With recent therapeutic advances survival of patients with β –thalassemia major, endocrine dysfunction becomes an important issue. Hypothalamic – pituitary and ovarian failure which present either with failure of puberty and primary amenorrhea or with secondary amenorrhea, is major problem in both adolescent and adult patients              (Al Rimawi et al., 2005). It is possible that early in the natural history of hypogonadotrophism, there is a transient reversible phase affecting GnRH-gonadotrophic hormones secretory dynamics. At this stage thalassemics may mimic other types of genetic iron storage disease (such as haemochromatosis), where the reversal of HH is possible (Chaterjee et al., 2000). 

Chaterjee et al. (2000) found low-normal GnRH stimulated gonadotrophin levels in 15 thalassemic girls who developed secondary amenorrhea. Studying the spontaneous pulsatile properties of LH, FSH in those thalassemic girls revealed progressive neurosecretory dysfunction of their gonadotrophins. Magnetic resonance imaging studies revealed structural abnormalities of the pituitary gland and its stalk in some of these patients.

Little is known about the ontogeny of hypothalamic-pituitary injury which ultimately causes such girls to cease having periods. Even during their menstrual cycles these patients had evidence of reduced spontaneous and induced gonadotrophin secretion. This is indicative of subtle damage to the hypothalamic GnRH pulse generator mechanism. Pituitary gonadotrophs suffered more severe damage than the hypothalamus. This early evidence of diminished H-P reserve suggested that they were likely to develop secondary amenorrhea at a late date. These thalassemic girls continued to have progressive deterioration in then H-P function within 2 years after the onset of amenorrhea. They had significantly lower GnRH stimulated gonadotrophin response, although no striking difference was observed in their basal gonadotrophin damage. Moreover the thalassemic girls had multiple pulse defects, marked diminution in amplitude and maximal levels, a significant increase in the percentage of sleep entrained pulses and the absence of pulse variability – characteristic of hypothalamic damage (Chatterjee et al., 1993).

Another striking point highlighted by Chatterjee et al. (1993), is that the derangement of H-P complex progresses in an irreversible fashion. Therefore, all patients who developed secondary amenorrhea became apulsatile for gonadotrophin secretion during the period of their study.

Investigations:

-         Routine biochemical analysis.

-         Bone age (x-ray on the wrist and hand)

-         Thyroid functions (TSH and FT4)

-         Hypothalamic-pituitary-gonadal functions:

§  GnRH stimulation test.

§  Sex steroids.

§  Pelvic ultrasound to assess ovarian and uterine size.

§  In selected cases, GH stimulation test.

§  In selected cases, insulin growth factor-1, insulin growth factor binding protein-3, plasma zinc (De Sanctis, 1995).

Treatment:

The treatment of delayed or arrested puberty and of hypogonadotrophic hypogonadism depends on factors such as age, severity of iron overload, damage to the HPG axis, chronic liver disease and the presence of psychological problems resulting from hypogonadism. Collaboration between endocrinologist and other doctors is critical.

For girls, therapy may begin with oral administration of ethinyl estradiol (2.5-5µg daily) for six months, followed by hormonal reassessment. If spontaneous puberty does not occur within six months after the end of treatment, oral oestrogen is re-introduced in generally increasing dosage (ethinyl estradiol from 5-10µg daily) for another 12 months. If breakthrough uterine bleeding does not occur, low oestrogen-progesterone hormone replacement is the recommended treatment (De Sanctis, 1995).

It is important that the treatment of pubertal disorders is treated on a patient-by-patient basis, taking account of complexity of the issues involved and the many associated complications (De Sanctis et al., 1995).