NEUROENDOCRINOLOGY

The endocrinology of reproduction in the female is more complex than in the male. While secretion of gonadotropins in females routinely occurs in a tonic fashion under negative gonadal feedback control, patterns of secretion are subject to more dramatic temporal fluctuations. Furthermore, tonic secretory release of gonadotropins is briefly interrupted by a massive output of gonadotropins (surge) preceding ovulation.

Mammalian females can be broadly categorized as either spontaneous or reflex (induced) ovulators. Spontaneous ovulatory cycles (ie., estrous or menstrual) occur independent of coitus; this system is controlled internally by integrated oscillations in balance of steroid hormones. Some mammals are induced to ovulate as a direct neural response to mating.

Brain-ovarian interactions. The hypothalamus of females contains two functional areas responsible for secretion of GnRH - the tonic (ARC) and surge (POA) centers. Follicular growth and luteal function are stimulated by tonic secretions of gonadotropins that occur in response to matched pulses of GnRH. Rate of tonic release of GnRH is modulated by inhibition enacted by follicular estradiol or luteal progesterone. A surge release of gonadotropins (positive feedback) is triggered either by estradiol (spontaneous females) or a mechanical stimulus (reflex females). The surge of gonadotropins causes ovulation and luteinization (Figure 4-39).

Reflex ovulation. The group of induced ovulators includes rabbits, ferrets, mink, voles, camels, domestic cats, the short-tailed tree shrew, and 13-lined ground squirrel. Reflex ovulators are the most efficient mammalian reproducers - ovulation and mating are timed accurately. Interestingly, coitus hastens the onset and prolongs the surge of LH in some species (eg., farm animals and primates) that ovulate spontaneously.

Females exhibit estrus when follicular growth supports circulatory concentrations of estradiol necessary to elicit receptivity. The signal for ovulation is sent from nerves innervating the reproductive organs and posterior torso to the GnRH surge center of the hypothalamus (Figure 4-40). Transection of the spinal cord blocks ovulation in animals that ovulate by mechanical perturbation.

Spontaneous cycles. Hormonal alterations during estrous and menstrual cycles are guided by the same set of basic rules of steroid hormone feedback (Table 4-3).

Episodic secretion of gonadotropins is inhibited to the greatest extent when circulatory levels of estradiol are low in the presence of progesterone; these effects are exerted on the hypothalamic tonic center. The surge in secretion of gonadotropins is elicited when circulatory concentrations of estradiol are high and progesterone is correspondingly low. It is hence apparent that centers for generation of GnRH in the female assume disparate (bimodal) sensitivities to estradiol.

There are two sites of action of estradiol in causing a preovulatory surge in gonadotropins - the rostral hypothalamus and anterior pituitary gland. The threshold for activation of the POA occurs once a sufficiently high level of circulatory estradiol is attained; consequently, there is a switch from negative to positive ovarian feedback. Estradiol also primes the pituitary response to GnRH by increasing synthesis and expression of receptors for GnRH. Therefore, not only is there a bolus increase in secretion of GnRH before ovulation, but the target for GnRH is very responsive; this accounts for the large magnitude (50- to 200-fold increase above baseline) of the surge.

Controversial research using rhesus monkeys has revealed that the surge center for secretion of gonadotropins resides primarily at the level of the anterior pituitary gland - the contention is that the POA remains dormant (ie., male-like), that the MBH oscillator of GnRH has a fixed frequency (one/hour), and that the positive feedback effect of estradiol is exerted solely on the gonadotrope; within this framework the obligatory role of the hypothalamus in the cyclic regulation of ovulation would be simplified - being that of a permissive "pacemaker."

Now to complicate the issue of ovarian positive feedback mechanisms even further. There is an acute increase in ovarian secretion of progestogens coinciding with the preovulatory surge of gonadotropins in some species (eg., rodents, rabbit, dog, pig, and primates). In rats the preovulatory follicle and ovarian interstitium secrete progesterone. It appears that a transient rise in progesterone facilitates the estradiol-induced surge of GnRH and pituitary responsiveness to GnRH; this is indeed a rather uncharacteristic (ie., positive feedback) role for progesterone.

Hormonal patterns and cause-and-effect relationships of a model spontaneous cycle are outlined in Figure 4-41. Hypothalamic negative feedback during a luteal phase (increase GnRH > LH > P4 > decrease GnRH > LH > P4 > increase GnRH ...) is analogous to the male norm (increase GnRH > LH > T > decrease GnRH > LH > T > increase GnRH ...). The decrease in circulatory progesterone associated with luteolysis breaks the chain of negative feedback that mandates the onset of a new cycle. A corresponding increase in tonic secretion of gonadotropins results in the terminal growth of a preovulatory follicle (multiple follicles in litter-bearing animals). The preovulatory follicle not only signals the hypothalamus, by way of estradiol, that it has matured, but has prepared itself to react to the upcoming surge of LH (FSH/estradiol causes induction of receptors for LH on granulosa cells). The pituitary gland and ovaries become refractory to tropic stimulation during the gonadotropin surge (receptors are internalized). With ovulation and formation of the CL, plasma concentrations of progesterone rise, and suppression of the hypophysiotropic centers is restored for the remainder of the cycle.

Gonadotropin patterns are usually in parallel during spontaneous cycles - both FSH and LH are regulated by GnRH. An abrupt divergence in secretory rates of gonadotropins occurs shortly after ovulation in species exhibiting estrous cycles. There is a dramatic decline in follicular production of inhibin with ovulation. An ensuing preferential elevation in FSH, the secondary surge, produces a spurt of follicular growth that otherwise would be constrained by low (luteal phase) levels of gonadotropins. An affected antral follicle is thereby advanced to a state of maturity so it can respond promptly to the increase in frequency and amplitude of gonadotropin pulses that commence with luteal regression.

Prolactin is also vulnerable to change during spontaneous cycles. The preovulatory rise in circulatory estradiol causes a surge in prolactin. Nevertheless, blockade of prolactin secretion does not interfere with cyclicity.

Follicular steroidogenesis. Receptors for FSH and LH in maturing follicles are concentrated on granulosa and thecal cells, respectively. Gonadotropins interact to stimulate receptive follicles to synthesize estradiol via a mechanism similar to that described for the male (theca interna = Leydig; granulosa = Sertoli). Androstenedione is the primary androgen secreted from thecal cells, which lack 17b -hydroxysteroid dehydrogenase; granulosa cells contain this enzyme (Figure 4-42).

The sharp decline in estradiol production by the preovulatory follicle that occurs coincident with the ascending limb of the gonadotropin surge is caused by a sudden fall in thecal 17a -hydroxylase and granulosa aromatase activities; estradiol itself has been implicated as an end-product enzymatic inhibitor. Steroidogenic function of follicular cells is reprogrammed during luteinization to favor of the delta-4 pathway (ie., synthesis of 3b -hydroxysteroid dehydrogenase and progesterone).