Obs & Gynae - Physiology Flashcards
In order to understand better the pathophysiology of menstrual disorders, it’s important to learn how the menstrual cycle works, and what hormones are responsible for regulating the activity of the menstrual cycle.
a) . What is the typical duration of the menstrual cycle?
b) . At what age do girls get their first menstruation? and at what age do females become menopausal?
a) . 21-35 days
b) . First menstruation (menarche): 11-15 yrs old
Menopause: 44-55 yrs old
What hypothalamic-pituitary axis is responsible for regulating the menstrual cycle?
The Hypothalamic-Pituitary-Gonadal (HPG) Axis
What hormones are released by the HPG axis in females?
What hormone is released in male?
Female: Hypothalamus –> GnRH –> anterior pituitary –> LH and FSH –> Gonads –> Oestrogen and Progesterone
Male: Everything is the same except that the gonad releases testosterone
What does FSH do in the menstrual cycle? (In other words, what is its role?)
- FSH binds to granulosa cells to stimulate follicle growth (hence the name Follicle-Stimulating Hormone)
- Converts androgens (produced by theca cells) to oestrogens
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Stimulates inhibin secretion from the granulosa cells of the ovarian follicles. The inhibin, in turn, suppresses FSH
- This is important as the inhibin being released prevents FSH from stimulating more than one dominant follicle. We just need one mature follicle for each menstrual cycle as women have only a finite number of eggs
What does LH do in the menstrual cycle? What role(s) does it play?
- Acts on theca cells to stimulate the release of androgens, which are then converted to oestrogen by granulosa cells (by FSH)
- LH surge triggers ovulation
- It maintains corpus luteum (see image) after ovulation
- The corpus luteum releases oestrogen, progesterone and inhibin in large quantities. It regresses after 12-14 days unless fertilisation takes place and hCG is released (after implantation) which prevents its breakdown
a) . What does oestrogen do in the menstrual cycle
b) . How does the level of oestrogen determine the level of GnRH secretion in the menstrual cycle?
Oestrogen is the predominant hormone in follicular phase:
- Oestrogen is released by granulosa cells as the follicle develops, hence, the more the follicle develops (the bigger it is), the more the oestrogen is released
- Low-to-moderate levels of oestrogen –> negative feedback on the HPG axis –> reduces GnRH secretion –> LH + FSH decreases
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High levels of oestrogen (in the absence of progesterone) –> positive feedback on the HPG axis –> increases GnRH secretion –> LH surge –> ovulation
- Note that the FSH levels will only increase slightly as it’s also being inhibited by inhibin)
- Oestrogen also causes LH receptors to be expressed on granulosa cells, so that after ovulation when the corpus luteum is formed, LH can act on granulosa lutein cells to produce progesterone during the luteal phase
- In the luteal phase, the corpus luteum releases oestrogen, progesterone and inhibin in large quantities. High levels of oestrogen in the presence of a high progesterone level –> negative feedback on the HPG axis –> reduces GnRH secretion –> LH + FSH decreases
What does progesterone do in the menstrual cycle?
Progesterone is the predominant hormone in luteal phase:
- Progesterone is produced by granulosa lutein cells of the corpus luteum in large quantities in response to LH
- It increases the inhibitory effect of low oestrogen and prevents the stimulatory effect of high oestrogen. Simply put, it promotes negative feedback on oestrogen to _**reduce GnRH when present_
Describe the physiology of the menstrual cycle. What happens in early follicular phase
Early follicular phase:
- At the start of the cycle, follicles development begins due to a rise in FSH
- FSH rises because the corpus lutuem from the previous cycle degenerates so it no longer produces any inhibin. Without inhibin, FSH level rises
- As the follicle develops i.e. gets bigger, the number of granulosa cells increases, and theca interna and externa appear
- Androgen production begins in the theca interna and then the granulosa cells convert the androgens to oestrogens, causing the oestrogen levels to rise. The endometrial lining, in response to a rising oestrogen, begins to thicken in the proliferative phase of the uterine cycle
- The oestrogen levels are still low at this stage as the follicle is still developing, so it inhibits GnRH secretion through negative feedback
What happens during late follicular phase?
Late follicular phase:
- As the follicle continues to develop under the influence of FSH, more granulosa cells are present and these cells produce increasing amounts of oestrogen and inhibin
- When the oestrogen reaches a level where it’s high enough to stimulate GnRH secretion from the hypothalamus through positive feedback, it causes LH to rise (LH surge). The FSH only rises a little as the inhibin being released prevents FSH from stimulating more than one dominant follicle (only one dominant follicle can survive and continue to maturity and complete each menstrual cycle, other follicles become polar bodies)
- The LH surge triggers ovulation where the secondary (mature) oocyte bursts out from the Graafian follicle and travels to the fallopian tube by fimbria. Here in the fallopian tube it remains viable for fertilisation for 24 hrs
- Oestrogen also causes LH receptors to be expressed on granulosa cells, so they become more responsive to LH
What happens in the early luteal phase of the menstrual cycle?
Early luteal phase:
- After ovulation, the ovarian follicle is luteinised to form the corpus luteum
- The granulosa lutein cells in the corpus luteum secretes oestrogen, progesterone and inhibin in large quantities. Increased oestrogen and progesterone help maintain the endothelial lining and turning it secretory (this is when the secretory phase of the uterine cycle starts). The inhibin inhibits the FSH, stalling the cycle in anticipation of fertilisation
- Secretory endometrium means that the cells on the inside of the uterus are producing substances necessary to support implantation of an egg should fertilisation occur
- Normally, the high levels of oestrogen alone would cause positive feedback on GnRH secretion, but the presence of progesterone (along with high oestrogen) promotes the negative feedback of oestrogen, inhibiting the GnRH secretion. Without GnRH, LH falls and the gamete doesn’t develop any further and it just sits in the ‘waiting phase’ ready to be fertilised
What happens in late luteal phase if:
a) . Fertilisation doesn’t occur
b) . Fertilisation occurs
Late luteal phase:
- a). After 14 days in the luteal phase, if fertilisation doesn’t occur the corpus luteum degenerates so the levels of oestrogen, progesterone and inhibin falls. Progesterone withdrawal means that the uterus lining is no longer maintained and sheds causing menstrual bleeding
- As the steroids fall, the negative feedback that inhibits GnRH secretion is lost, so LH and FSH begins to rise again and the cycle restarts. (Note that LH may not rise at all as the follicles are just starting to develop, so oestrogen level is really low. FSH will rise due to a lack of inhibin)
- (b). If fertilisation and implantation take place, the syncytiotrophoblast of the embryo produces human chorionic gonadotrophin hormone (hCG) that exerts luteinising effects and so prevents the breakdown of corpus luteum. The corpus luteum continues to secrete oestrogen and progesterone until the placenta takes over the production of these steroid hormones at around 4 months of gestation
The duration of the menstrual cycle varies from one individual to another, but most people have a menstrual cycle of 21-35 days.
Which phase of the menstrual cycle is responsible for giving this variation?
The follicular phase
(The luteal phase is ALWAYS the same in every woman, lasting 14 days, so what gives this variation in the duration of the menstrual cycle is the follicular phase. Some women have shorter follicular phase while others have slightly longer follicular phase)
There are 2 layers of the endometrium. What are they? Which layer is the one that sheds during menstruation?
Stratum functionalis (this layer sheds during menstruation)
Stratum basalis (this layer allows the functional layer to regrow when a new cycle begins)
Describe the uterine cycle. What phases are there?
Proliferative phase:
The endometrium proliferates so the stratum functionalis thickens in response to oestrogen produced by the ovary. Simple, straight glands develop inside the endometrium but as this phase continues the stratum functionalis of the endometrium becomes even thicker and the glands become coiled
Secretory phase:
After ovulation, the glands become more pronounced and coiled and become secretory (so mucus gets thickened) due to progesterone
Towards the end of this phase, when the hormones produced by the corpus luteum falls, the glands lose their structure and the endometrium sheds its functional layer
Menses:
It occurs in the absence of fertilisation once the corpus luteum has broken down and the internal lining of the uterus is shed. Menstrual bleeding usually lasts between 2-7 days with 10-80 mL blood loss
Which hormone (oestrogen vs progesterone) regulates the follicular/ proliferative phase of the menstrual cycle?
Oestrogen
What physiological changes does oestrogen bring during the follicular/ proliferative phase?
Role of oestrogen in follicular/ proliferative phase:
- Stimulate mildly anabolic metabolic changes, depress appetite and maintain bone structure
- Increased growth and motility of the myometrium
- Thickening of the endometrium and increase in number and size of glandular invaginations. The cells secrete a watery fluid conducive to sperm
- Thin alkaline cervical mucus to facilitate sperm transport
- Increased secretion and muscular contraction in the fallopian tube
- Increased growth and motility of fallopian cilia
- Increased mitotic activity in the vaginal epithelium
What physiological changes does progesterone bring during the luteal/ secretory phase?
Role of progesterone in luteal/ secretory phase:
- Stimulate a mildly catabolic metabolic change, elevates basal body temperature, promote change in salt and water excretion which may, in combination with oestrogen lead to net Na+ and water retention
- Further thickening of the endometrium, increased secretion and development of spiral arteries
- Further thickening of the myometrium but reduces myometrial motility (you want a stable environment for the zygote to grow)
- Reduces fallopian tube motility, secretion and cilia activity
- Thick acidic cervical mucus, inhibiting sperm transport to prevent polyspermy
a) . Describe the process of spermatogenesis
b) . How long does the process take?
Spermatogenesis:
Men start producing sperm as they approach puberty, which is usually from 10-16 yrs old
a) . Sperm production begins in the seminiferous tubules of the testes
* The primordial germ cells (PGCs) in the germinal epithelium give rise to Type A dark spermatogonia (2n), cells that initiate spermatogenesis
* Type A dark spermatogonia (2n) –> mitosis –> Type A pale spermatogonia (2n) –> mitosis –> Type B spermatogonia (2n)
* Type B spermatogonia (2n) –> mitosis –> some more spermatogonia (to keep the bank full so that they won’t lose the source of spermatogonia) + 1o spermatocytes (2n)
* 1o spermatocytes (2n) –> meiosis I –> 2o spermatocytes (n)
* 2o spermatocytes (n) –> meiosis II –> spermatids (n)
* Throughout the series of mitotic and meiotic events, cytokinesis (cell separation) is incomplete, which means that successive cell generations remain joined together by cytoplasmic bridges (i.e. they maintain contact throughout differentiation)
* The spermatogonia and spermatids remain embedded deep within the sertoli cells throughout their development. This way, the Sertoli cells can support, protect, and nourishes the spermatogonia and the spermatids with nutrition, and also assist in the maturation of spermatids into spermatozoa (spermiogenesis) and the subsequent release of the spermatozoa
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Spermatogenesis is regulated by LH secreted by the pituitary gland
- LH binds to Leydig cells around each seminiferous tubule and stimulates the secretion of testosterone which in turn binds to Sertoli cells to promote spermatogenesis
- FSH is also produced - it binds to Sertoli cells and stimulates testicular fluid production and synthesis of androgen receptor proteins
(b) . Spermatogenesis takes about 70 days, therefore in order for sperm production to be continuous and not intermittent, multiple spermatogenic processes are occurring simultaneously within the same seminiferous tubule, with new groups of spermatogonia arising every 16 days (spermatogenic cycle). Each of these populations of spermatogenic cells will be at different stages of spermatogensis. This ensures that men will always be ready to procreate when females are the most fertile around the time of ovulation
To illustrate the process of spermatogenesis better, please see the image attached!
I have attached below an image of what germinal epithelium looks like in a male. You can see that one germinal epithelial cell consists of the basement membrane which forms the wall of the seminiferous tubule, cells belonging to the spermatogenic cell lineage (they eventually form spermatozoa), and Sertoli cells
1 = Basement membrane
2 = Spermatogonia
3 = 1o spermatocyte
4 = 2o spermatocyte
5 = Spermatid
6 = Mature spermatid
7 = Sertoli cell
8 = Tight junctions
What is spermiogenesis?
Describe the process of it
Spermiogenesis is the final stage of spermatogenesis, which sees the maturation (remodelling and differentiation) of spermatids into mature spermatozoa. Changes include:
- Formation of the acrosome - contains enzymes that assist in penetration of the egg and its surrounding layers (zona pellucida) during fertilisation
- Condensation of the nucleus
- Formation of the neck, middle piece, and tail
- Shedding of most of the cytoplasm as residual bodies that are phagocytosed by Sertoli cells
- When spermatozoa are fully formed, they enter the lumen of the seminiferous tubules and are pushed towards the epididymis by contractile elements in the wall of the seminiferous tubules and are stored there
Describe the process of oogenesis
Oogenesis differs from spermatogenesis in that it begins before birth
Before birth
- Primordial germ cells (which originate in the yolk sac of the embryo) migrate to the primordial female gonad and differentiate into oogonia
- These oogonia (all derived from a single cell) are arranged in clusters surrounded by follicular cells, originating from surface epithelium covering the ovary - see image
- Oogonia undergo a number of mitotic divisions to produce 1o oocytes (2n) and more oogonia (to keep the bank full so that they won’t lose the source of oogonia). The 1o oocytes then undergo meiosis I BUT are arrested at prophase I
- During the next few months, replication of mitosis peaks at around 20 weeks, causing a rapid increase in the number of oogonia and 1o oocytes (about 7 million of them!). Cell death then occurs after this peak leaving just 2 million 1o oocytes at birth
- Primary oocytes are arranged in the gonad as clusters and each of them has follicular cells surrounding it - we now call these ‘primary follicles’
During childhood
- During childhood, further atresia occurs, leaving just 40,000 eggs by the beginning of puberty, and < 500 of them will be ovulated
At puberty
- Once puberty begins, a number of 1o oocytes (15-20 of them) begin to mature each month, BUT only one of them reaches full maturation to become an oocyte
- The 1o oocytes undergo 3 stages:
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Pre-antral stage
- The 1o oocyte is still in meiosis I but will grow significantly in this stage
- The follicular cells grow and proliferate to form a stratified cuboidal epithelium - we now call these ‘granulosa cells’, they secrete glycoproteins that form the zona pellucida around the 1o oocyte
- Surrounding connective tissues also differentiate to become the theca folliculi, a specialised layer of cells that is responsive to LH and can secrete androgens under its influence
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Antral stage
- Fluid-filled spaces form between granulosa cells, these eventually combine together to form a central fluid filled space called the antrum - we now call the follicles ‘secondary follicles’
- In each month, one of these secondary follicles becomes dominant and develops further under the influence of FSH, LH and oestrogen
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Pre-ovulatory stage
- Induced by the LH surge
- Meiosis I of 1o oocyte is now complete, giving rise to a haploid 2o oocyte and the 1st polar body (far less cytoplasm)
- The haploid 2o oocyte and the polar body then undergo meiosis II. The initial polar body will replicate to give 2 polar bodies BUT the 2o oocyte arrests in metaphase II - this happens 3 hrs before ovulation!
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Pre-antral stage
- The 1o oocytes undergo 3 stages:
- During ovulation, an LH surge occurs and increases collagenase activity. The collagenase breaks down the collagen in the follicular wall. This, in combination with muscular contractions of the ovarian wall, results in the 2o oocyte being released from the Graafian follicle inside the ovary. The 2o oocyte is then taken up into the fallopian tube via the fimbriae, ready to be fertilised
- If no fertilisation occurs, the 2o oocyte degenerates 24 hrs after ovulation, remaining arrested in meiosis II. However, if fertilisation does take place, the 2o oocyte completes meiosis II to form a haploid ovum and a 3rd polar body (which later disintegrates)
- The Graafian follicle becomes the corpus lutuem. The corpus lutuem is maintained for the first 16 weeks of pregnancy by the hormone Human Chorionic Gonadotropin (hCG) as it secretes progesterone that maintains the endometrium for implantation
- The endometrium will eventually become part of the placenta
Give 5 differences between spermatogenesis and oogenesis
See table attached!
What physiological changes are made to the sperm and the ovum so that the two can fertilise?
Sperm
In order for sperm to penetrate the oocyte, it has to undergo capacitation, which involves:
- Acrosomal reaction (see image) - where the membrane surrounding the acrosome fuses with the plasma membrane of the sperm’s head, exposing the contents of the acrosome. The contents include surface antigens necessary for binding to egg’s cell membrane, and numerous enzymes that are responsible for breaking through the egg’s tough coating (zona pellucida) and allowing fertilisation to occur (fusion of the nucleus of the sperm and ovum).
- Changing the tail movement from a beat-like action to a thrashing whip-like action to help propel the sperm forward.
Ovum:
- Contains cell surface glycoproteins called ZP3 proteins. They interact with the capacitated sperm and allow the acrosomal enzymes to be released from the acrosome. The acrosomal enzymes break down the zona pellucida, allowing the sperm nucleus to fuse with the ovum nucleus
Describe the indifferent stage in the embryonic development of male and female gonads
- At first, the intermediate mesoderm gives rise to a pair of urogenital ridges, one on each side. They initially do not contain any germ cells
- In the 4th week, primordial germ cells (PGCs) begin to migrate from the yolk sac along the dorsal mesentery of the hindgut to the urogenital ridges in the retroperitoneum. They reach the urogenital ridges by the 6th week
- Primitive sex cords are formed within the urogenital ridges, and together with PGCs they form an indifferent gonad meaning that it’s the same primordial gonad regardless of XX or XY
Describe how an indifferent gonad develop into a male gonad
In a male embryo, the XY sex chromosomes are present. The Y-chromosome contains the SRY gene that stimulates the development of the primitive *sex cords (medullary cords) to become the testis cords. The thick tunica albuginea forms around the cords
- A portion of the testis cords breaks off to form the future rete testis
- The remaining cords contain 2 types of cells:
- Germ cells (spermatogonia, spermatocytes, spermatids, spermatozoa)
- Sertoli cells
- These 2 types of cells together form the germinal epithelium
- In puberty, these cords acquire a lumen and become the seminiferous tubules, the site of spermatogenesis
- Located between (or just outside) the testis cords are the Leydig cells (derived from intermediate mesoderm). In the 8th week, they begin producing testosterone which drives differentiation of the internal and external genitalia
*Sex cords are structures that develop from the urogenital ridges
Please see the image attached for the illustration of the anatomies described in the embryonic development of testes
See image!
The image on the right shows the cross-section of the seminiferous tubules, you can clearly see a lumen in the centre of the seminiferous tubules. The lumen is where spermatozoa leave the germinal epithelium. The sperm then travel through the seminiferous tubules into the rete testis and then the ductili efferentes before being stored in the epididymis until ejaculation
Before males reach puberty, the seminiferous tubules don’t have a lumen yet, but once they reach puberty, they acquire a lumen!
You can also see that leydig cells are lying just outside the seminiferous tubules
Describe how internal genitalia develop for males and females?
- In the first weeks of urogenital development, all embryos have 2 pairs of ducts, one on each side, both draining into the urogenital sinus part of the cloaca. These are the:
- Mesonephric (Wolffian) ducts
- Paramesonephric (Mullerian) ducts
- The fate of these ducts depends on whether there is a functional testis
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Male
- In the presence of testosterone (produced by the Leydig cells), the mesonephric ducts remain and develop to form the efferent ductules, epididymus, vas deferens and seminal vesicles
- The Sertoli cells of the testes produce Mullerian-inhibiting hormone (MIH) which inhibits Mullerian (paramesonephric) ducts development, so they degenerate
- Its developmental remnant is the appendix testis (also called Hydatid of Morgagni), a small portion of tissue located on the upper pole of each testicle, which has no function at all
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Female
- In females, there are no Leydig cells to produce testosterone. In the absence of this hormone, the mesonephric ducts degenerate, leaving behind only a vestigial remnant called the Gartner’s duct
- Lack of MIH allows the Mullerian (paramesonephric) ducts to remain and develop. These ducts have 3 parts:
- Cranial - becomes the Fallopian tubes
- Horizontal - becomes the Fallopian tubes
- Caudal - fuses to form the uterus, cervix and the upper 1/3rd of the vagina
- The lower 2/3rd of the vagina is formed by the sinovaginal bulbs (derived from the pelvic part of the urogenital sinus - hindgut endoderm)
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Male
If there is a lack of fusion of the paramesonephric ducts, what uterine defects can it potentially cause?
The most common uterine defect is bicornuate uterus where there are 2 uteruses sharing a common single vagina. As it’s asymptomatic, the condition is often only picked up on an USS during pregnancy. It’s associated with a high risk of miscarriage and premature delivery
Other uterine defects are shown in the image attached
Describe the development of external genitalia in males and females
Indifferent stage
- The development of the external genitalia begins in the 3rd week
- Initially, the external genitalia is indifferent with 3 basic components:
- Genital tubercle
- Genital folds - urethral folds (anterior) + anal folds (posterior)
- Genital swellings on either side of the urethral folds
- They then develop differently after this stage and this depends on whether or not dihydrotestosterone is produced
- In male embryoes, the production of DHT causes
- Rapid elongation of the genital tubercle –> phallus
- Anteriorly, the urethral folds fuse to form urethral groove - the folds close over by the 4th month, forming the penile urethra
- Genital swellings –> scrotal swellings (moving caudally to eventually form the scrotum)
- In female embryoes, this is driven by oestrogens
- The genital tubercle only elongates slightly to form the clitoris
- The urethral folds do not fuse, creating the vaginal orifice and labia minora
- Genital swellings form the labia majora
- In male embryoes, the production of DHT causes
What is the name of condition called where there are one or more abnormal openings of the urethra along the inferior side of the penis?
Hypospadias - due to incomplete closure of the urethral folds during development. Very common (around 1 in 300 births)
Surgery is needed to correct this defect
