ENDOCRINOLOGY OF THE REPRODUCTIVE SYSTEM, PUBERTY AND MENOPAUSE

M. Djauhari Widjajakusumah

The Hypothalamic-Pituitary Unit

GnRH Neurons in The Hypothalamus

Arcuate Nucleus

Important region for gonadotropin control in primate The driver of the reproductive system Generates and releases pulses of GnRH into the portal venous system

Median Eminence

GnRH granules are transported by axonal flow to the median eminence area; the most prominent projections are from arcuate neurons. GnRH is released into capillaries Long Portal Veins pituitary stalk adenohypophysis (anterior pituitary) Direct brain - anterior pituitary vascular connection rapid transport of undiluted minute amounts of GnRH

The GnRH Pulse Generator

Arcuate nucleus

The foremost ventral portion of the medial basal hypothalamus

The most essential neural center controlling gonadotropin secretion Lessions of the arcuate nucleus abolished basal release of LH and FSH Increase in arcuate nucleus electrical activity precedes LH discharge Subject to modifying influences from extra- and intra-hypothalamic loci
Griffin, J.E., Ojeda, S.R.: Textbook of Endocrine Physiology 3 rd ed 1996.

The GnRH Pulse

GnRH is released in pulsating fashion, concomitantly stimulates LH and FSH secretion Synchronized pulse of GnRH release and pulse of LH release:

Intermittent (fluctuated) LH release, ultradian (less than 1 day) rhythm Oscillate with a period of about 1 hr; 2 hrly between peaks
Lower amplitude of FSH pulse than that of LH: smaller amounts of FSH released in response to GnRH pulse longer FSH half-life individual pulses masking effects on the subsequent ones estradiol suppress FSH release at the pituitary level more evident in the early follicular phase, postmenopausal period, ovariectomized individuals (low estradiol conditions)

Synchronized pulse of GnRH release and pulse of FSH release:

Gonadotropin-Releasing System

Adenohypophysis gonadotroph cells

Cells secrete only LH, or only FSH, or both Particularly LH Episodes 70-100 mnts Interpulse intervals 1 hr (circhoral rhythm) Less frequent during the luteal phase (progesterone effect?) Sleep-related rhythm (diurnal rhythm) increased LH release during sleep fundamental feature at the onset of puberty A function of hypothalamic LHRH
Griffin, J.E., Ojeda, S.R.: Textbook of Endocrine Physiology 3 rd ed 1996.

Pulsatile secretion of gonadotropins

ADOLESCENCE AND PUBERTY

Adolescence

The period of growth and maturation of the reproductive system that culminates at puberty
The final maturation of of the reproductive system activated by pituitary gonadotropins Secretory and morphological activities of the gonads reach the adult stage, and the menarche occurs

Adolescence and Puberty

Puberty

Refers to the process of physical changes by which a child's body becomes an adult body capable of reproduction The period when the endocrine and gametogenic functions of the gonads have first developed to the point where reproduction is possible Thelarche: development of breasts Pubarche: development of axillary and pubic hair Menarche: the first menstrual period Generally anovulatory Regular ovulation about a year later

Control of The Onset of Puberty

The precise mechanism is still not well understood Requires interactions between the brain, the pituitary gland, and the gonads and their target organs

Childrens gonads can be stimulated by gonadotropins Childrens pituitary contain gonadotropins, but are not secreted Childrens hypothalami contain GnRH During the period from birth to puberty, a still unknown neural mechanism is preventing the normal pulsatile release of GnRH

CONTROL OF THE ONSET OF PUBERTY

THE NEURAL INPUT

The neuroendocrine GnRH system is fully mature at birth adult level of gonadotropin secretion Pulsatile GnRH activity declines in late infancy until the prepubertal /adolescence phase (hypothalamic quiescence) The initial step that leads to puberty is an restored increase in the pulsatile release of GnRH gonadotropins release puberty Proper release of GnRH may require synchronous activity of specific neuronal system

CONTROL OF THE ONSET OF PUBERTY

THE METABOLIC INPUT

Good nutrition advances the onset of puberty, starvation delays it

Link between nutrition and the activity of GnRH pulse generator

The hypothesis: a threshold of body weight (percent of body fat) is critical for allowing initiation of the maturity process

Probably metabolic cues are relayed to the brain and provide signals that activate the GnRH pulse generator

Reinitiation of Pulsatile Gonadotropin Secretion in Pubertal Children

The first sign of the initiation of sexual maturation Low gonadotropin secretion during day-time, increased during the night In the later stages of puberty Nocturnal increase of gonadotropin levels replaced gradually by episodic increase around the clock

The possible relation between melatonin and the onset of puberty Melatonin is argued to inhibit the onset of puberty in humans; its effects vary markedly from species to species (inhibition facilitation)

Puberty as a hormonal process

1.

The brain's hypothalamus begins to release pulses of GnRH. True puberty is often termed "central puberty" because it begins as a process of the central nervous system Cells in the anterior pituitary respond by secreting LH and FSH into the circulation The ovaries or testes respond to the rising amounts of LH and FSH by growing and beginning to produce estradiol and testosteron Rising levels of estradiol and testosterone produce the body changes of female and male puberty

2.

3.

4.

PRECOCIOUS PUBERTY

Pubertal changes before the age of 8 years Isosexual precocious puberty: sexual development is consistent with genetic sex Heterosexual precocious puberty: sexual development is inconsistent with genetic sex ( virilism)

True precocious puberty

Pseudoprecocious puberty

PRECOCIOUS PUBERTY

TRUE PRECOCIOUS PUBERTY

The gonads are the source of the sex hormones Premature activation of the hypothalamic-pituitary unit Secondary sex characteristics with gametogenesis

PSEUDOPRECOCIOUS PUBERTY

Primary ovarian / testes (gonadal) abnormality independent of pituitary stimulation Leydig cell tumors of testis Granulosa cell tumors of ovary Adrenal (extragonadal) Androgen-secreting tumors (in males) Estrogen-secreting tumors (in females)

DELAYED PUBERTY

Lack of physical manifestation of puberty beyond the norm of pubertal age (17 in females, 20 in males)

Organic causes

CNS disorders: delay in activation of the hypothalamic pulse generator Gonadotropin deficiency Gonadal failure (dysgenesis) Nutrtion Weight Stress Exercise

Environmental factors

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