THE PUBERTY PAGE!

In order to better appreciate the changes in the hypothalamic-pituitary-gonadal axis and the reproductive endocrine profiles which result in puberty, it is necessary to trace the development of the reproductive endocrine axis to its beginnings in the fetus.  You may wish to review these constructs (female, male).

The Fetal Hypothalamic-Pituitary-Gonadal Axis

We normally think of the "period of the fetus" as beginning when the fetus diverges from the common mammalian embryo and it becomes possible to macroscopically identify the species of the fetus. We will say just a bit more about the period of the oocyte, the period of the embryo and the period of the fetus when we talk about gestation. The rudimentary fetal hypothalamus may secrete GnRH as early as 5-6 weeks of gestation. Leydig (interstitial) cells of the male gonad may be functional and secreting androgens by as early as 60-65 days of gestation. Ovarian organogenesis occurs at 11-12 weeks of gestation in the female fetus. Fetal pituitary gonadotropes are present as early as 12 weeks of gestation in the male and female fetus, at which time fetal LH and FSH are detectable (near the conclusion of the first trimester of gestation). LH and FSH are being secreted in biologically active concentrations by about 20 weeks of gestation. By mid-gestation, the fetal pituitary is secreting gonadotropins in an unrestricted fashion in the absence of ovarian steroid feedback. In other words, gonadotropins are high and secreted in patterns similar to those in gonadectomized (free of gonadal steroid negative feedback) adults.

An increase in gonadotropin secretion from 12-20 weeks of gestation coincides with development of the pituitary portal vasculature (ie. as the pituitary-portal vasculature develops, GnRH is transported to the pituitary with increasing efficiency).  The gonads respond to the gonadotropins by producing and secreting steroid hormones but the pituitary and hypothalamus are not yet sensitive to steroid feedback at this time (presumably the population of steroid receptors in the pituitary is not adequate to respond to the steroids and so there is little negative feedback on gonadotropin secretion during this time).  During the second half of gestation, the hypothalamus and pituitary begin to develop steroid receptors and so the hypothalamus and pituitary become increasingly sensitive to negative feedback effects of the gonadal steroids. The gonadotropins tend to fall throughout the second half of gestation. The decline in gonadotropins gradually reduces the stimulus for fetal gonadal steroidogenesis, although hCG from the chorionic villi of the placenta will continue to stimulate fetal gonadal steroid secretion.  hCG is "human chorionic gonadotropin.  hCG binds and stimulates exactly the same receptors that are stimulated by LH.  We sometimes refer to LH receptors as LH/hCG receptors.  You may have heard of hCG before... it is the hormone we test for when we use "early pregnancy detection kits, such as those purchased at the corner drug store.

Shortly after birth (the neonatal or infantile phase), spurts of LH and FSH are detectable in neonatal circulation, possibly because the newborn infant has been removed from the steroid-rich uterine environment. While the maternal environment is rich in progestins and estrogens, the decrease in exposure to maternal estrogens is particularly important in increasing gonadotropin secretion during the neonatal phase. Testosterone may be elevated for several months in newborn males. During the first few months to years of life, the hypothalamic-pituitary axis gradually becomes "exquisitely sensitive" to negative feedback by gonadal steroids and, perhaps, inhibin.  During this period, the gonad slowly shuts down the hypothalamic-pituitary axis (GnRH-LH/FSH axis). This, in turn, reduces the gonadotropin stimulation of steroid production. The result is that both gonadal steroid and gonadotropin concentrations achieve a new lower homeostatic balance. These new lower gonadotropin and gonadal steroid concentrations will be maintained until puberty.  We say that the reproductive axis has been "inactivated."

The Childhood (Infant) Hypothalamic-Pituitary Gonadal Axis

The childhood (see Bing Crosby at 4 years of age) stage begins sometime between birth and 2 years of age, and continues until the peripubertal period; in terms of reproductive physiology, this stage begins when the reproductive axis has been successfully inactivated shortly following birth.  During this period, the hypothalamic-pituitary- gonadal axis remains quiescent, although it should be remembered that the pituitary and gonad are functional.  Maintenance of the low steroid and gonadotropin concentrations depends on at least 2 things.  The first is maintenance of the exquisite sensitivity of the pituitary to gonadal steroid negative feedback.  The second factor involves a component of CNS activity which exerts a "braking effect" on the hypothalamic GnRH pulse generating system. This braking system, which slows the frequency of GnRH secretion involves endogenous opioid peptides in the CNS, particularly the action of b-endorphin from the arcuate nucleus of the hypothalamus.  Endogenous opioid peptides are small proteins with morphine-like activity.

 

The Peripubertal-Adolescent Hypothalamic-Pituitary-Gonadal Axis

puberty with a critical body composition

It has been hypothesized that attainment of menarche is related to attainment of a critical body fat composition. This hypothesis seems to be really oversimplified, but is in fact strongly supported by evidence obtained in humans and domestic mammals.  Certainly, we recognize that females suffering malnutrition may become oligomenorrheic or amenorrheic.  The same condition often occurs in highly trained female athletes with reduced body fat, although the specific causes of the condition may vary somewhat from that in malnutrition or starvation, including a number of eating disorders.

the central gonadostat hypothesis

Something happens when a child approaches the age of puberty, whether it is because of the chronological age of the CNS, or due to some critical body composition. Whatever the reason, suppression of GnRH by endogenous opioids is gradually lost.  Recall that endogenous opioids are peptides with morphine-like activity produced by the brain and pituitary.  A new, higher set-point at which GnRH secretion is more frequent is achieved.  Essentially, the opioid brakes on central hypothalamic maturation are removed.  The new, higher frequency of GnRH secretion begins to wake the reproductive axis which was nearly completely "inactivated" during the very early childhood period.

re-awakening of the pituitary-gonadal axis

As the pituitary is gradually exposed to more GnRH, the pituitary becomes less sensitive to negative feedback by estrogen.  The pituitary achieves a new higher set-point for gonadotropin secretion.  These changes are gradual.  Initially, there is an increase in the frequency of gonadotropin secretion during sleep.  Over a period of several months to a few years, the frequency of episodes of gonadotropin secretion also increases during the day.  Eventually, a new higher frequency of gonadotropin secretion is observed during daytime and night-time. In humans, the frequency of gonadotropin (LH) secretion is about the same during daylight and darkness.

Menarche & gonadarche (peripubertal gonadal steroidogenesis)

Gonadarche is a term used to refer specifically to the elevation in functional steroidogenesis in the peripubertal period. Estrogens tend to rise in females between 8 and 13 years of age. Androgens rise in males between 9 and 14 years of age.  Typically, females achieve puberty earlier than males; this is reflected in height data for female and male peripubertal growth spurts. Associated with the overall increase in gonadotropin secretion during the peripubertal period is the ability of follicles to develop beyond the early antral stages and through the gonadotropin dependent stages to the preovulatory (or Graafian) stage.  As puberty progresses we will see that LH pulses are eventually followed by somewhat pulse-like release of androgens in males, estrogens in females and eventually, progesterone in females in the luteal phase.  When gonadotropin stimulation is sufficient to drive follicles through the antral stages of development (see below), the follicles will produce increasing amounts of estrogens.  When estrogens are maintained high enough for long enough, they will exert positive feedback effects on the hypothalamic-pituitary axis and ovulation becomes possible.  Regular ovulation may not be attained during the first year following the attainment of estrogen positive feedback (ie. several "anovulatory cycles" may occur).  Attainment of estrogen positive feedback and ovulation is the final event marking onset of puberty in females.  Adolescence and the associated development of secondary sexual characteristics with exposure to new, adult levels of gonadal steroids, may last several years. Attainment of mature androgen levels and onset of spermatogenesis reflect gonadarche in males.

Sex hormone binding globulins (SHBG's)

Over 95% of the gonadal steroids in circulation are bound by protein carrier molecules, the sex-hormone binding globulins (SHBGs). In males, gonadotropin stimulation of the testes becomes sufficient to support androgen production from the Leydig (interstitial) cells and spermatogenesis within the seminiferous tubules.  Herein lies another important consideration with respect to the action of gonadal steroids (androgens) in the male. In both males and females, most estrogens and androgens are bound to SHBGs in circulation.  In males, SHBG concentrations drop in the peripubertal period to about half that present in female circulation. With 20 times the androgen production of the female and only half the circulating SHBGs, bioactive testosterone levels in males are about 40 times higher than in females. This has led to the rather unique hypothesis of a condition which has been referred to in the literature as "testosterone toxicity" in males.  Some people suggest that this explains a "biological tendency for males to behave aggressively."