Morphological features of the hypothalamus and pituitary gland are similar for males and females across species. Later it will become evident there are salient distinctions between sexes in the physiological virtues of the hypothalamic-pituitary regulatory network.

Structural organization. The hypothalamic-pituitary axis is located at the base of the brain; it is bordered by four distinct landmarks - the thalamus (cranially), optic chiasm (rostrally), sphenoid bone (caudally), and mammillary body (dorsally). The pituitary gland lies encased within a depression in the sphenoid bone called the sella turcica ("Turkish saddle") (Figure 2-1).

The hypothalamus is a composite of bilaterally-oriented pairs of diencephalic nuclei and associated unmyelinated axons situated within the walls and floor of the third ventricle (use of the term "nuclei" in this context refers to discrete groups of cell bodies of neurons). Nuclei within the hypothalamus have been charted and named. For the sake of simplicity, I will deal only with those hypothalamic nuclei known to have a crucial role in reproduction.

Two hypophysiotropic regions link the hypothalamus to functional activities of the pituitary gland - the rostral and medial basal hypothalami. The rostral hypothalamus contains nuclei involved in production of GnRH (preoptic area) and oxytocin (supraoptic and paraventricular nuclei). The preoptic area is of functional significance during the preovulatory (GnRH-surge) phase in females. The principal nucleus (arcuate) implicated in pulsatile (tonic) production of GnRH is accommodated within the medial basal hypothalamus (MBH). Nerves of the preoptic area and arcuate nucleus discharge within the median eminence; this area marks the boundary of the hypothalamus with the anterior lobe of the pituitary gland (Figure 2-2).

Terminals of neurons that produce GnRH also have been traced laterally to a discrete region along the inner wall of the third ventricle - the organum vasculosum of the lamina terminalis (OVLT). Therefore, an alternative route for output of GnRH might be into the cerebrospinal fluid of the third ventricle. Specialized ependymal cells lining the floor of the ventricle (tanycytes) extend to the capillary network of the median eminence; these cells can transport substances between the third ventricle and median eminence.

Neurons that produce GnRH originate within the epithelium of the olfactory pit and migrate into the brain (Kallman's syndrome is a genetic hypogonadotropic hypogonadism [GnRH deficiency] disorder associated with anosmia [inability to smell] that is caused by failure of fascicles of the olfactory nerve complex to make synaptic contact with the forebrain).

The pituitary gland originates from two different sources of embryonic ectoderm - oral and neural. Oral ectoderm evaginates from the antecedent of the palate (Rathke's pouch), detaches, and migrates toward the developing brain (ie., before formation of the skull) assuming a position apposed to a downward projection of the third ventricle (tuber cinereum). Rathke's diverticulum differentiates into pars distalis, tuberalis, and intermedia (adenohypophysis; adeno = glandular). The pars distalis and tuberalis make up what is commonly designated the anterior lobe. Pars tuberalis is a small outgrowth of the pars distalis that collars the infundibular stalk - which suspends the pituitary gland within the sella turcica (Figure 2-2). The wall of Rathke's pouch forms the pars intermedia (intermediate lobe) - a source of melanocyte-stimulating hormone (MSH, melanotropin).

The pars nervosa, also called the neurohypophysis or posterior lobe (see Table 2-1 for a summary of anatomical terminology), is an extension of the central nervous system (CNS) (Figure 2-3). Axons of the supraoptic and paraventricular nuclei pass through the infundibular stalk and into the neurohypophysis (Figure 2-2). Nerve fibers are beset by specialized astroglial cells called pituicytes. Oxytocin is stored within nerve terminals of the neural lobe.

Unlike the posterior pituitary gland, the anterior lobe is not a continuum of the hypothalamus. A specialized vascular (portal) system is formed which allows for direct endocrine communication between the hypothalamus and anterior pituitary gland (Figure 2-2). A portal network is one in which vein-like vessels provide an uninterrupted connection between two capillary beds without intervening heart and lungs. Some neurohormones, such as GnRH, have very short plasma half-lives (< 1 minute) and would be inactivated before reaching the adenohypophysis via the systemic circulation.

Capillary beds of the portal system are located within the median eminence (primary plexus) and anterior pituitary gland (secondary plexus). Portal vessels originate at the primary plexus, traverse the infundibular stalk, and end within the secondary plexus. The superior hypophyseal artery serves the primary plexus. The majority of blood accessing the anterior lobe is derived from the primary plexus. Hypothalamic hormones are released into the primary plexus and transported to the anterior pituitary gland (Figure 2-4). In some mammals an inferior branch of the hypophyseal artery enters the anterior pituitary gland directly. Some researchers have contended that blood flow within the portal system can occur in the reverse (retrograde) direction - from anterior lobe toward hypothalamus. Therefore, the pituitary gland might regulate the hypothalamus by "short-loop" feedback. Finally, there are nerves and short portal vessels that interconnect the pituitary lobes, thus forming potential routes of intrapituitary communication.

The anterior pituitary lobe is composed of a heterogeneous population of cells arranged in irregular cords and masses; these cells are in close contact with an elaborate microcirculatory system (Figure 2-5). Cells of the anterior lobe have been broadly classified based on their staining characteristics as chromophils (having cytoplasmic granules) or chromophobes (which do not stain intensely). Chromophils are further subdivided as basophils (darkly stained) and acidophils (eosinophilic or reddish stained). Basophils synthesize FSH, LH, thyroid-stimulating hormone (TSH, thyrotropin), and adrenocorticotropic hormone (ACTH, corticotropin). Acidophils synthesize prolactin and growth hormone (GH, somatotropin). Chromophobes are the predominant cellular type within the gland; they are thought to be inactive progenitors of the chromophils. Subpopulations of glandular cells of special interest in reproduction are the gonadotrope (produces FSH and LH) and lactotrope or mammotrope (produces PRL). Immunocytochemical methods employing specific antisera against a particular hormone are necessary to distinguish between gonadotropes, lactotropes, thyrotropes, corticotropes, and somatotropes.

Adenomas (benign tumors) involving lactotropes (prolactinomas) are the most common pathology of the hypothalamic-pituitary axis. Presence of tumor is diagnosed by radiographic techniques (conventional radiography, computed tomography scan, or magnetic resonance imaging) in combination with endocrinological testing. Enlarged tumors can cause visual defects by impinging on the optic chiasm. If growth of the pituitary tumor cannot be controlled by drugs (eg., with bromocryptine, a dopamine agonist), it can be removed by surgery. To expose the sella turcica, an incision is made under the upper lip and the floor of the sphenoid sinus is resected with the aid of an operating microscope (the mortality rate for this procedure by experienced neurosurgeons is about 1%). With complete hypophysectomy, hormonal replacement therapy may be necessary for management of adrenocortical crisis, hypothyroidism, and(or) diabetes insipidus (excretion of large quantities of urine due to inadequate output of antidiuretic hormone).

Negative steroid feedback. Animals become competent to reproduce as they make their transition through the puberal phase. Before the onset of puberty, gonadotropin production is depressed; this is caused by intensified hypothalamic sensitivity to the negative feedback effect of low levels of circulatory steroid hormone (testosterone in males and estradiol in females). During the puberal period responsiveness of the hypothalamus to the inhibitory action of steroid hormone becomes blunted - secretion of GnRH and gonadotropins is boosted and gonadal activity is initiated.

Fertility is not a permanent attribute, but can be curtailed. On-off fluctuations are typical in mammals that exhibit restricted breeding seasons, are nursing offspring, or are under intermittent physical or mental stresses. Most available data indicates that shifts in breeding activities are dictated by alterations in hypothalamic sensitivity to gonadal steroid hormone negative feedback. Disparate modulatory signals (eg., those related to emotional state, body condition [nutrient restriction or excess], photoperiod, or lactational status) can evidently converge upon a common target - the GnRH-producing neuron (Figure 2-6). With inhibition of pulsatile secretion of GnRH, there is a corresponding decline in secretion of gonadotropins leading to hypogonadism. Gonadal function is reinstated when the hypothalamic response to inhibitory steroid hormone is attenuated - the hypothalamic "gonadostat" is reset and the fertile/breeding phase can start anew.