Hormonal Control of the Menstrual Cycle
- Overview of the Menstrual Cycle Components
  - Phases of the Ovarian Cycle
  - Gonadotrophic Hormone Levels
  - Ovarian Cycle Events
  - Ovarian Hormone Levels
  - Uterine Cycle
  - Phases of the Uterine Cycle
  - Basal Body Temperature (°C)
- Menstrual Cycle Phases and Anatomy
  - Key Phases
- Normal Menstrual Cycle Manifestation and Control
- The Hypothalamus
- Hypothalamus-Pituitary-Ovary-Uterus Feedback Loop
- Initial Stages of Follicular Development
  - Gonadotropin-Independent Growth
  - Follicle Development Stages
- Follicular and Luteal Phases Visual Overview
- Cellular Interactions in Follicle Steroid Production
- Androgen and Estrogen Synthesis
- Follicle Growth and Feedback
  - Follicle Maturation and Hormonal Influence
- Hormonal Interactions
  - Regulation of Ovarian Hormones
    - Diagram Labels
- Summary of Hormone Feedback and Cellular Action
  - Cycle Phases
- Ovulation
  - Mechanism of Ovulation
- Luteal Phase
  - Corpus Luteum Formation and Regression
- Cycle Renewal and Hormone Feedback
- Phases of the Woman’s Cycle
  - Associated Hormones
  - Cycle Phases (Repeated)
- The Endometrium
  - The Proliferative Phase
  - The Secretory Phase
  - Endometrial Receptivity
  - Endometrial Tissue Sections
- Menstruation
  - Physiological Mechanism of Menstruation
  - Endometrial Repair
- Puberty
  - Physical Changes in Puberty
  - Tanner Stages
    - Breast Development
    - Pubic Hair Development
Puberty Disorders
- Precocious Puberty
  - Central Precocious Puberty (True Precocious)
  - Peripheral Precocious Puberty (Pseudopuberty)
    - McCune-Albright Syndrome
  - Investigations and Treatment
    - Investigations
    - Treatment
- Delayed Puberty
  - Causes
  - Hypogonadotropic Hypogonadism (Central)
  - Hypergonadotropic Hypogonadism (Gonadal Failure)
    - Causes:

Hormonal Control of the Menstrual Cycle

By dr Mona Ahmed

Normal Menstrual Cycle Manifestation and Control

Manifestation of normal menstrual cycle Is: Presence of regular vaginal bleeding as a result of

➡️ shedding of the endometrial lining following
➡️ failure of fertilization.

The cycle depends on: Changes occurring in ovarian hormones

Which controlled by:

Pituitary
Hypothalamus

The hypothalamo–pituitary–ovarian axis (HPO). Hormonal abnormalities lead to menstruation abnormalities.

28 Days Menstrual phase (5 days)

The Hypothalamus

Secretes gonadotrophin-releasing hormone (GnRH)
- which controls hormone secretion in the:
  - anterior pituitary gland
    - ✓ luteinizing hormone (LH)
    - ✓ follicle-stimulating hormone (FSH)
- ➤ GnRH released in a pulsatile pattern
- ➤ This process is modulated by the ovarian sex steroid hormones
  - oestrogen and progesterone

Hypothalamus-Pituitary-Ovary-Uterus Feedback Loop

N.B. the mechanism of action of the negative feedback of oestrogen is uncertain

Initial Stages of Follicular Development

Gonadotropin-Independent Growth

The initial stages of follicular development are independent of hormone stimulation.

Follicular development will fail at the preantral stage and follicular atresia will ensue if pituitary hormones LH and FSH are absent.
➢FSH levels rise in the first days of the menstrual cycle, when oestrogen, progesterone and inhibin levels are low.
• This stimulates a cohort of small antral follicles on the ovaries to grow.

Follicle Development Stages

Follicular and Luteal Phases Visual Overview

Cellular Interactions in Follicle Steroid Production

Within the follicles, there are two cell types that are involved in the processing of steroids, including oestrogen and progesterone.
These are the theca and the granulosa cells, which respond to LH and FSH stimulation, respectively.Z
Theca cells ➡️ LH stimulates Progesterone.
Granulosa cells ➡️ FSH stimulates Oestrogen.

Androgen and Estrogen Synthesis

LH stimulates production of androgens (from cholesterol) within theca cells. …These androgens are converted into oestrogen in granulosa cells, under the influence of FSH.

FSH = follicle-stimulating hormone | LH = luteinising hormone

Follicle Growth and Feedback

As the follicles grow, oestrogen secretion increases, leading to negative feedback (on the pituitary) which causes a decrease in FSH secretion. (This assists in selection of the dominant follicle while smaller follicles will undergo atresia).

Follicle Maturation and Hormonal Influence

Hormonal Interactions

Regulation of Ovarian Hormones

Inhibin is secreted by granulosa cells, enhancing androgen synthesis.
Activin is secreted by granulosa cells (is structurally similar to inhibin, but has an opposite action), increasing FSH binding on the follicles.
Insulin-like growth factors (IGF-I, IGF-II): highest levels found in the dominant follicle fluid towards ovulation.
Kisspeptins: proteins recently found to play a role in regulation of the HPO axis, mediated in metabolism of leptin.
Leptin (affect hypothalamus) plays a role in energy production, weight and reproductive health.
” Mutations in the kisspeptin receptors associated with delayed or absent puberty”.

Summary of Hormone Feedback and Cellular Action

Ovulation

At the end of the follicular phase (which lasts an average of 14 days), the dominant follicle has grown to approximately 20 mm (mature follicle).

✓FSH induces LH receptors on the granulosa cells.
✓ Oestrogen increases until making a positive feedback effect on the pituitary.
✓LH surge (24–36 hours later).
✓ Progesterone from the mature follicle provides feedback for secretion, causing a small periovulatory rise in FSH.

Mechanism of Ovulation

Ovulation occurs after breakdown of the follicular wall. The LH surge is a predictor of ovulation. This process is under the influence of LH, FSH, and proteolytic enzymes (prostaglandins PGs). Inhibition of PG production may result in failure of ovulation. Thus, women wishing to become pregnant advised to avoid taking PG synthetase inhibitors, such as aspirin and ibuprofen.

Luteal Phase

✓After release of oocyte, the remaining granulosa and theca cells form the corpus luteum (CL) (due to accumulated yellow pigment).
✓Why? To supply granulosa cells with rich blood for steroidogenesis.
✓Progesterone stabilizes the endometrium in preparation for pregnancy.
✓High Progesterone levels suppress FSH and LH, which prevent another follicular growth.
✓The luteal phase lasts 14 days in most women; it is relatively constant in all women.
✓In the absence of βhCG (pregnancy), the CL will regress (luteolysis), leading to progesterone withdrawal, and shedding of the endometrium and menstruation.

Corpus Luteum Formation and Regression

Cycle Renewal and Hormone Feedback

Reduction in levels of progesterone, oestrogen and inhibin feeding back to the pituitary cause increased secretion of gonadotrophic hormones.
New preantral follicles begin to be stimulated and the cycle begins again.

Phases of the Woman’s Cycle

The Endometrium

The hormone changes effected by the HPO axis during the menstrual cycle will occur whether the uterus is present or not.
The changes in the endometrium give the most obvious external sign of a regular cycle.

The Proliferative Phase

After menstruation, when glandular and stromal growth begin. The epithelium lining the endometrial glands cells increase by mitoses. Endometrial thickness increases from 0.5 mm to 3.5–5 mm at the end of the proliferative phase.

The Secretory Phase

After ovulation (around day 14)
there is a period of endometrial glandular secretory activity.
Endometrial thickness does not increase any further.
The glands will become more tortuous.
Spiral arteries will grow.
Fluid is secreted into uterine lumen.
Later, formation of a temporary layer, known as the decidua, in the endometrial stroma.

Endometrial Receptivity

After day 21–22, a progesterone-dependent stage making the endometrium receptive for embryo implantation.

Endometrial Tissue Sections

(A)proliferative phase.
(B)secretory phases Of the menstrual cycle

Menstruation

Menstruation (day 1) is the

shedding of the ‘dead’ endometrium and ceases as the endometrium regenerates (which normally happens by day 5–6 of the cycle).
Immediately prior to menstruation, three layers of endometrium can be seen.
The basalis is the lower 25% of the endometrium, which will remain throughout menstruation and shows few changes during the menstrual cycle.
The midportion is the stratum spongiosum with oedematous stroma and exhausted glands. The superficial portion (upper 25%) is the stratum compactum with prominent decidualized stromal cells.

Physiological Mechanism of Menstruation

A fall in circulating levels of oestrogen and progesterone 14 days after ovulation leads to loss of tissue fluid, vasoconstriction of spiral arterioles and distal ischaemia. This results in tissue breakdown and loss of the upper layers, along with bleeding from fragments of the remaining arterioles, seen as menstrual bleeding. Enhanced fibrinolysis reduces clotting. (This effect can be reproduced artificially, for example in patients taking the COCP).

Vaginal bleeding will cease after 5–10 days as arterioles vasoconstrict and the endometrium begins to regenerate.

Haemostasis in the uterine endometrium is different from elsewhere in the body (no clot formation and no fibrosis).

Endometrial Repair

NOTE Endometrial repair involves:

both glandular and stromal regeneration
and angiogenesis
to
reconstitute the endometrial vasculature.

Puberty

Is the process of reproductive and sexual development and maturation that changes a child into an adult.
During childhood, the HPO axis is suppressed and levels of GnRH, FSH and LH are very low.RR
From the age of 8–9 years GnRH is secreted in pulsations of increasing amplitude and frequency.
These are initially sleep-related, but as puberty progresses, these extend throughout the day. This stimulates secretion of FSH and LH by the pituitary glands, which in turn triggers follicular growth and steroidogenesis in the ovary.
The oestrogen produced by the ovary then initiates the physical changes of puberty. The exact mechanism of onset of puberty is still unknown, but it is influenced by many factors including race, heredity, body weight and exercise.
Leptin plays a permissive role in the onset of puberty.

Physical Changes in Puberty

breast development (thelache), first physical signs of puberty are breast budding 2–3 years before menarche
pubic (adrenarche), dependent on the secretion of adrenal androgens and is usually after thelarche
axillary hair growth
growth spurt (growth hormone secretion +GRH & androgens)
onset of menstruation (menarche).

Leptin (metabolic hormones produced by adipose tissue in response to fat deposition) plays a role in puberty.
The mean age of menarche is 12.8 years.
Initial cycles are usually anovulatory and can be irregular (may take over 3 years to be regular).
Pubertal development was described by Tanner, and the stages of breast and pubic hair development are often referred to as Tanner stages 1–5.
The absence of menstruation is called amenorrhoea and may be primary or secondary.

Tanner Stages

Breast Development

Prepubertal
Breast and papilla are elevated as a small mound. Areolar diameter increases.
Further enlargement of the breast bud with loss of the contour separation between breast and areola.
Areola and papilla form a secondary mound.
Mature areola is part of the general breast contour.

Pubic Hair Development

Prepubertal
Sparse, lightly pigmented, chiefly along the medial border of the labia majora.
Darker, beginning to curl, increased amount spreading over the mons.
Increased amount of coarse, curly but limited to the mons.
Adult feminine triangle with spread to the medial surface of the thighs.

Puberty Disorders

Precocious Puberty

Onset of puberty before the age of 8 in a girl or 9 in a boy. It is classified as either central or peripheral.

1. Central Precocious Puberty (True Precocious)

Gonadotrophin dependent. The aetiology is often unknown (75% idiopathic), up to 25% are due to central nervous system (CNS) malformations or brain tumours.

2. Peripheral Precocious Puberty (Pseudopuberty)

Gonadotrophin independent, is always pathological and can be caused by

oestrogen secretion:

✓ Exogenous oestrogen ingestion.
✓ Hormone-producing tumour.
✓ McCune Albright syndrome.

McCune-Albright Syndrome

Polystostotic fibrous dysplasia.
Café au lait skin lesions.
Precocious puberty. McCune-Albright syndrome involves the GNAS gene at locus 20q13 (p, q). More information: genetics4medics.com/mccune-albright-syndrome.html

Investigations and Treatment

Investigations

✓ Serum gonadotrophin (elevated in central and low in peripheral).
✓ Brain images.
✓ Pelvic US.

Treatment

✓ GNRH analoge.
✓ Surgery.

Delayed Puberty

When there are no signs of secondary sexual characteristics by the age of 14 years.

Causes

Central defect (hypogonadotropic hypogonadism).
Failure of gonadal function (hypergonadotropic hypogonadism).

Hypogonadotropic Hypogonadism (Central)

Gonadotrophins are:

Constitutional.
Anorexia nervosa.
Excessive exercise.
Chronic illness (diabetes or renal failure).
Pituitary tumour.
Kallman’s syndrome.

Associated with delayed puberty and primary amenorrhoea.

Hypergonadotropic Hypogonadism (Gonadal Failure)

Gonadotrophins are: The gonad does not function.

Causes:

Turner syndrome.- XO
XX gonadal dysgenesis.
Premature ovarian failure at any age (including prior to pubertal age):
- Idiopathic.
- Autoimmune.
- Metabolic disorder.
- Following chemo- or radiotherapy for childhood cancer.