Neuro-Endocrine Regulation & Physiological Periods

Neuro-endocrine Regulation of the Menstrual Cycle

Menstrual cycle is a complex set of cyclical processes in a woman's reproductive system and body aimed at reproduction. Its external sign is regular blood discharge from the genital tract, or menstruation. The cycle lasts from 21 to 35 days, averaging 28 days, and tends to be consistent for each woman.

Reproductive System

The reproductive system is a functional system involving a dynamic organization of bodily structures and processes. It has central and peripheral components that interact in a hierarchical manner, where feedback mechanisms allow underlying structures to either inhibit or enhance the function of overlying ones.

Five Levels of the Female Reproductive System

  1. Target Tissues and Organs: genitalia, mammary glands, skin, hair follicles, fat, and bone tissue.

  2. Ovaries: Responsible for generative and hormonal functions.

  3. Anterior Pituitary Gland: Secretes hormones that regulate ovarian function.

  4. Hypophysotropic Zone of the Hypothalamus: Controls the anterior pituitary gland.

  5. Extrahypothalamic Brain Structures: limbic system, hippocampus, and amygdala, which integrate external and internal stimuli.

The first level contains cytoreceptors specific to sex steroid hormones like estradiol, progesterone, and testosterone. Endometrium experiences the most changes due to these hormones. The functional layer of the endometrium undergoes cyclical changes, while the basal layer facilitates the restoration of the functional layer after menstruation.

Endometrium Changes During the Menstrual Cycle (Four Phases)

  1. Desquamation: Occurs with a sharp decline in estrogen and progestogen levels due to the regression of the corpus luteum. This leads to the shedding of the necrotic functional layer.

  2. Regeneration: Restoration of the functional layer from basal elements under the influence of gradually increasing estrogen levels, completing around the fourth day.

  3. Proliferation: Continues from the 5th to the 14th day, driven by markedly increasing estrogen levels, causing the endometrium to thicken from 1–2 mm to 10 mm.

  4. Secretion: Lasts for 14 days. After ovulation, the corpus luteum produces estrogen and progesterone. Progesterone receptors increase while estrogen receptors decrease in endometrial cells, inhibiting proliferation. (These last two phases define the menstrual cycle as biphasic.)

Second Level - Ovaries

The ovaries have generative and hormonal functions with the follicular apparatus as the main structure. Follicles exist in different developmental stages:

  1. Primordial (embryonic) Follicles: Characterized by a single layer of flat pregranular cells and a small oocyte.

  2. Preantral (primary, secondary) Follicles: Primary follicles contain a primary oocyte, a single layer of cubic cells, zona pellucida, and a forming theca. Secondary follicles contain multiple layers of granulosa cells and a theca differentiated into inner and outer layers.

  3. Antral (tertiary) Follicles: Development is stimulated by FSH from the pituitary gland, reduced EGF, and enhanced IGFR 1 and 2, stimulating granulosa cell division and differentiation. These cells are then sensitized to estradiol and FSH. They also secrete estrogen and inhibin. A decrease in FSH leads to atresia in less developed antral follicles.

  4. Preovulatory/Mature Follicle: Only one follicle continues to develop. Estradiol, FSH, collagenase, prostaglandins, oxytocin, and relaxin levels sharply increase in the follicular fluid. A rapid increase in estradiol leads to an LH surge, and to a lesser extent FSH, causing ovulation – the rupture of the follicle and release of the oocyte, which occurs about 12 hours after the LH peak.

The entire process from primordial to ovulatory state is about 85 days. After ovulation, capillaries grow into the follicle, and granulosa cells luteinize, forming the corpus luteum, which primarily secretes progesterone, estradiol, and inhibin.

If fertilization does not occur, LH decreases, causing yellow body regression, which lasts about 14 days. The corpus albicans forms over 1–2 months. If pregnancy occurs, chorionic gonadotropin supports the corpus luteum, and it produces sex hormones (estrogens, progesterone) and androgens.

Steroid hormones fluctuate: estradiol is low in the early cycle, gradually rises with follicle growth, rises sharply pre-ovulation, decreases in the luteal phase, and drops sharply before menstruation. Progesterone remains low in the follicular phase, rises slightly pre-ovulation, and increases rapidly after ovulation, decreasing sharply before menstruation. Androgen levels remain low and constant.

Third Level - Anterior Pituitary Gland

Gonadotrophs secrete FSH and LH, which affect ovarian receptors. FSH stimulates follicle growth and maturation, granulosa cell proliferation, estrogen secretion, formation of FSH and LH receptors, aromatase levels, and production of inhibin, activin, and insulin-like growth factors. LH stimulates androgen secretion by theca cells, facilitates ovulation with FSH, and transforms granulosa cells into lutein cells, which promote progesterone synthesis in the corpus luteum.

Production of gonadotropins is regulated by the hypothalamus. FSH and LH levels fluctuate during the menstrual cycle. Prolactin (PRL) from the adenohypophysis stimulates mammary gland growth and lactation and has a fat-mobilizing and hypotensive effect. Increased prolactin can inhibit follicle growth and steroid synthesis. Dopamine inhibits prolactin secretion, while estrogens stimulate it, slightly increasing prolactin levels in the periovulatory period and the luteal phase.

Fourth Level - Hypothalamus

This level consists of ventro- and dorsomedial arcuate nuclei neurons. These nerve cells have neurosecretory activity and produce gonadotropin-releasing hormone (Gn-RH), also known as gonadoliberin or luliberin. Gn-RH secretion occurs in pulses about once every 1-3 hours, initiated around puberty. Catecholamines (noradrenaline, dopamine), indolamine (serotonin), and opioid peptides regulate Gn-RH secretion. Norepinephrine is stimulatory, while dopamine, serotonin, and opioid peptides are inhibitory.

Fifth Level - Extrahypothalamic Structures of the Brain

This level perceives impulses from external and internal environments. Internal influences are perceived via specific sex hormone receptors for estrogens (mainly estradiol), progesterone, and androgens. Neurotransmitters and neuropeptides influence the hypophysotropic zone of the hypothalamus. Neurotransmitters such as norepinephrine, acetylcholine, and GABA stimulate Gn-RH release, while dopamine and serotonin inhibit it.

Neuropeptides, especially endogenous opioid peptides (endorphins, enkephalins, and dynorphins), also regulate the reproductive system. Increased levels of these peptides suppress Gn-RH synthesis and, consequently, LH and FSH. The reproductive system's functional state is determined by the connections of its subsystems, that are a long loop (ovarian hormones - the nucleus of the hypothalamus), a long loop (ovarian hormones - adenohypophysis), a short loop (adenohypophysis - hypothalamus) and ultr-short loop (gonadoliberin - neurocytes of the hypothalamus).

Physiological Periods of a Woman's Life

Distinct periods characterized by age-related anatomical and physiological traits:

  1. Newborn Period: The first 10 days with influence of maternal estrogens, followed by a release of FSH and LH due to decreased estrogen. Proliferative changes in the endometrium and possible scanty secretions occur. By the 10th day, all signs of estrogenic influence disappear.

  2. Childhood: Up to 8 years. Ovaries have minimal activity. The uterus is small, and the cervix exceeds the size of the uterus. Around ages 3-4, the uterus descends into the small pelvis. The hypothalamic-pituitary-ovarian system is immature.

  3. Puberty: Ages 8 to 17. Reproductive system matures, divided into prepubertal and two pubertal phases. This phase involves activation of the hypothalamic-pituitary system, leading to development of genitalia and feminization. The first monthly period, menarche, occurs, and at about age 17-18 maturity is reached allowing for conception, pregnancy, childbirth, and breastfeeding.

  4. Reproductive Period: Ages 17-18 to 45. Reproductive system functions optimally for reproduction.

  5. Perimenopause: Years before menstruation ceases, including 1 year after the last period, (menopause) with declining ovarian function. The average menopause age is 51 years and is defined as confirmed after a year.

  6. Postmenopause: After menopause characterized by a sharp decrease in estradiol and atrophic changes.