Repro Flashcards
Sexual Differentiation & Disorders by Dr Gillott
What is sexual determination?
*LOB: Outline the different ways in which gender and / or sex can be defined
Genetically controlled process dependent on the switch on the Y c.s
C.s determination of female/ male
Sexual Differentiation & Disorders by Dr Gillott
What is sexual differentiation?
*LOB Outline the different ways in which gender and / or sex can be defined
The process by which internal and external genitalia develop as male or female
Determined by molecular switch
Consist of several stages
Sexual Differentiation & Disorders by Dr Gillott
What is genotypic sex?
*LOB Outline the different ways in which gender and / or sex can be defined
Whether the 23 c.s is X or Y
Are you XX or XY?
Sexual Differentiation & Disorders by Dr Gillott
What is gonadal sex?
*LOB Outline the different ways in which gender and / or sex can be defined
Are testes or ovaries present?
May not align with genotypic sex?
Sexual Differentiation & Disorders by Dr Gillott
What is phenotypic sex?
*LOB Outline the different ways in which gender and / or sex can be defined
Biological appearance
May not be congruent with other sex
Sexual Differentiation & Disorders by Dr Gillott
What is legal sex?
*LOB Outline the different ways in which gender and / or sex can be defined
Whats on your passport/ birth certificate?
Act of parliament 2004
Sexual Differentiation & Disorders by Dr Gillott
What is gender identity?
*LOB Outline the different ways in which gender and / or sex can be defined
How you feel, express yourself
Sexual Differentiation & Disorders by Dr Gillott
What does the Y c.s contain?
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Gene for SRY
Sex Determining Region Y
Sexual Differentiation & Disorders by Dr Gillott
What is SRY
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Transcription Factor
Switches on SRY
Approx Week 7
Makes gonad into a Testis
On the P arm
Sexual Differentiation & Disorders by Dr Gillott
SRY develops testis which develops ___
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
anti-Mullerian Hormone (AMH)
Testosterone
Sexual Differentiation & Disorders by Dr Gillott
Gonadal Development
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
After fertilisation pair of gonads develop that are bipotential
Genital Ridge (somatic mesenchymal tissue)
Mullerian Duct (upper 1/3 of the uterus, uterine tubes, female internal genitalian)
Wolffian Duct (seminal vesicle, vas deferens, epididymus)
Remember swap them around M for Women, W for Men
Sexual Differentiation & Disorders by Dr Gillott
How does the gential ridge develop?
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
3 waves of cells
Primordial Germ Cells -> sperm (m) or oocytes (f)
Primitive Sex Cords -> Sertoli (m) or Granulosa (f)
Mesonephric -> Leydig (m) or Theca (f)
Sexual Differentiation & Disorders by Dr Gillott
What is primordial germ migration?
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Small cluster of cells in epithelium of yolk sac
Approx 3 weeks
Migrate to connx tissue of hindgut approx 6 weeks
Sexual Differentiation & Disorders by Dr Gillott
What are primitive sex cords?
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Surface of genital ridges migrate inwards to meet primordial germ cells
In men SRY
In Women no SRY
Sexual Differentiation & Disorders by Dr Gillott
Compare primitive sex cords in Male and Female
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Sexual Differentiation & Disorders by Dr Gillott
What are mesonephric cells
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Influenced by surrounding cells
Originate from mesonephric primordium (lateral to genital ridge)
MALE: Vascular tissue, Leydig Cells, Basement of seminiferous tubules and rete-testis
FEMALE: Vascular tissue, Theca Cells
Sexual Differentiation & Disorders by Dr Gillott
Summarise Gonadal Sex
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Sexual Differentiation & Disorders by Dr Gillott
What is internal reproductive organs?
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Mullerian ducts
* most important in female
* inhibited in the male by AMH
Wolffian ducts
* most important in the male stimulated by testosterone
* lack of stimulation by testosterone means regression in female
Selection in Male driven by AMH and testosterone
Selection in Female driven by lack of AMH and testosterone
Sexual Differentiation & Disorders by Dr Gillott
What is External Differentiation?
5-a-reductase
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
In the skin, Testosterone is converted by 5-a-reductase to produce DHT (Dihydrotestosterone)
5-a-reductase present in M and F but no testosterone in F
DHT is strong and binds to the testosterone receptor
DHT causes differentiation of the male external genital
Sexual Differentiation & Disorders by Dr Gillott
How does the male external genitalia form?
5-a-reductase
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
In the skin, Testosterone is converted by 5-a-reductase to produce DHT (Dihydrotestosterone)
DHT is strong and binds to the testosterone receptor
DHT causes differentiation of the male external genitals
- Clitoral area enlarges into penis
- Labia fuse and become ruggated to form scrotum
- Prostate forms Testosterone Dihydrotestosterone
Sexual Differentiation & Disorders by Dr Gillott
Summarise Sex Differentiation
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Sexual Differentiation & Disorders by Dr Gillott
What cells produce AMH?
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Sertoli
Sexual Differentiation & Disorders by Dr Gillott
Which cells produce Testosterone
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Leydig Cells
Sexual Differentiation & Disorders by Dr Gillott
Lack of SRY
*LOB Describe the process of sexual differentiation and the chromosomal and endocrine factors that control it
Ovary
and Granula cells
Sexual Differentiation & Disorders by Dr Gillott
What is Gonadal dysgenesis
*LOB Relate the process of sexual differentiation to clinical disorders
Incomplete differentiation
Missing SRY (male)
Partial or complete deletion of second Y (female)
Used as general word for abnormal development
Sexual Differentiation & Disorders by Dr Gillott
What is sex reversal?
*LOB Relate the process of sexual differentiation to clinical disorders
Phenotype not congruent with genotype
Sexual Differentiation & Disorders by Dr Gillott
What is intersex?
*LOB Relate the process of sexual differentiation to clinical disorders
Components of both tracts or ambiguous genitalia
Sexual Differentiation & Disorders by Dr Gillott
Patients prefer terms
*LOB Relate the process of sexual differentiation to clinical disorders
Disorder of Sexual Differentiation
NOT ‘pseudohermaphrodite’ or ‘testicular feminisation’
Sexual Differentiation & Disorders by Dr Gillott
What happens if….
XY
Testosterone has no effect
*LOB Relate the process of sexual differentiation to clinical disorders
SRY present
Sertoli produce AMH
AMH regresses Mullerian
Leydig produce Testosterone
Testosterone DOESNT develop Wolffian
DHT present
DHT doesnt produce external genitals
ANDROGEN INSENSITIVITY SYNDROME
1:20,000
Phenotypically female
AFAB
Primary amenorrhea, lack of body hair
Often ID as female
Why no external? Same receptor, Receptor broken
Sexual Differentiation & Disorders by Dr Gillott
What is
ANDROGEN INSENSITIVITY SYNDROME
*LOB Relate the process of sexual differentiation to clinical disorders
1:20,000
Phenotypically female
AFAB
Primary amenorrhea, lack of body hair
Often ID as female
Undecended testes (U/s)
“Male” Karyotype
Not surgically reassigned unless option explored w gender ID.
Partial AIS
Why no external? Testosterone receptor broken
Sexual Differentiation & Disorders by Dr Gillott
What if XY
but 5α reductase deficiency
*LOB Relate the process of sexual differentiation to clinical disorders
SRY present
Sertoli and AMH present
Leydig and Testosterone present
Normal internal stucture- epididymus, testis
Testosterone to DHT fails
External genitalia -> phenotypically feminine
No fusion of labial scrotal folds
No testicular decent
Sexual Differentiation & Disorders by Dr Gillott
What if is 5α reductase deficiency
*LOB Relate the process of sexual differentiation to clinical disorders
Incidence varies as autosomal recessive
Degree of enzyme block varies and therefore so does presentation
High testosterone and adrenarche may cause distress
Sexual Differentiation & Disorders by Dr Gillott
What if 45 XO
*LOB Relate the process of sexual differentiation to clinical disorders
XO
Ovaries
Female External genitalia
Failure of ovarian function
TURNER SYDNROME
May be fertile, may be moasaicism
Small ovaries with growth defects and development
Hormone support of bones and uterus required.
Sexual Differentiation & Disorders by Dr Gillott
What is Turner Syndrome?
*LOB Relate the process of sexual differentiation to clinical disorders
45 XO
Ovaries
Female External genitalia
Failure of ovarian function
May be fertile, may be moasaicism
Small ovaries with growth defects and development
Hormone support of bones and uterus required.
Sexual Differentiation & Disorders by Dr Gillott
Why does Tuner Syndrome cause errors but X repression is natural
*LOB Relate the process of sexual differentiation to clinical disorders
45XO has error
but 46XX has natural repression of one X
But cross over for psuedoautosomal region at the gene
Has a biological impact on expression
? full purpose unknown
Sexual Differentiation & Disorders by Dr Gillott
What if XX Female exposed to high androgen in utero
*LOB Relate the process of sexual differentiation to clinical disorders
Congenital adrenal hyperplasia
Dont be scared of Steroids
Produces Ovary
Doesnt produce AMH- Mullerian (internal female)
Testosterone so Wollfian grow as well
DHT present- external male genitalia
Sexual Differentiation & Disorders by Dr Gillott
Understanding Steroidogenesis
*LOB Relate the process of sexual differentiation to clinical disorders
Cholesterol
3 6-sided rings
1 5-sided ring
And a chain
All the progestorins are 3 6-sided rings and 1 5-sided ring. They dont have the chain
How they differentiate? The enzymes move where the oxygens live
Remove 2 more carbons: Have all the androgens like testosterone. How are they different? Enzymes move where the Oxygens live
Remove 1 more carbon: You have Oestrogens!!!!
Name ends with -one??? Ketone so has =o
Name ends with -iol?? Has 2 OH groups
Sexual Differentiation & Disorders by Dr Gillott
What if no cortisol?
*LOB Relate the process of sexual differentiation to clinical disorders
Adrenal glands cannot transform the cholesterols.
No cortisol? High levels of ACTH
Lots of cholesterol brought in
Progestorins build up
Androgens build up in foetus adrenal cortex
Produces lots of testosteone
(no oestrogen as aromatase not present)
Sexual Differentiation & Disorders by Dr Gillott
Aromatase is not present in females
*LOB Relate the process of sexual differentiation to clinical disorders
Until puberty
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is the hypothalamus and pituitary?
Describe the hormonal control and principle of feedback in coordinating the hypothalamus -pituitary-gonadal axis
Neuroendocrine
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
Hypothalamic / Pituitary / Gonadal Axis
Describe the hormonal control and principle of feedback in coordinating the hypothalamus -pituitary-gonadal axis
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is kisspeptin?
Describe the hormonal control and principle of feedback in coordinating the hypothalamus -pituitary-gonadal axis
Kisspeptin was found to play a role in hypogonadotropic hypogonadism around 2003 and its involvement in the hypothalamic pituitary axis and sexual maturation was uncovered.
Influences Hypothalamus to release GnRH
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is kisspeptin neruones
Describe the hormonal control and principle of feedback in coordinating the hypothalamus -pituitary-gonadal axis
Connect to GnRH
Express kisspeptin
? Role in puberty
Smae amino terminal but different sizes
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
How does Kisspeptin link to HPGAxis?
Describe the hormonal control and principle of feedback in coordinating the hypothalamus -pituitary-gonadal axis
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
How is GnRH secreted?
*LOB Understand the importance of pulsatile GnRH secretion and how this has been pharmacologically exploited
Pulsatile release
30-120 minutes
Stimulates LH and FSH
Slow Pulse: FSH > LH (F for fast but its actually slow)
High Pulse: LH > FSH
If given constantly- shuts down the pituitary
Receptor is G Protein so decouples G Protein from secondary messenger
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
Pituitary
*LOB Detail the key hormones of the HPG axis and the mechanisms controlling their synthesis and secretion
FSH and LH released in response to GnRH
Proteins
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
How does HPG Axis links into the other axis
*LOB Detail the key hormones of the HPG axis and the mechanisms controlling their synthesis and secretion
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is puberty
*LOB Describe the two endocrine processes of puberty
Transition from non-reproductive to reproductive state
Profound physiological and psychological changes
Secondaary characteristics development
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
Two events occur at puberty
*LOB Describe the two endocrine processes of puberty
Adrenarche
From the adrenal glands
maturation of cells
Release of androgens leads to pubarche: appearance of pubic and axillary hair
Gonadarche
Follows adrenarche
HPG Driven
LH FSH
Activate gonadal function
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
Roles of LH and FSH
*LOB Describe the two endocrine processes of puberty
LH
stimulates gonadal steroid synthesis and secondary sex characteristics
FSH
stimulates growht of testis and folliculogenesis with steroid synthesis
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is adrenarche?
*LOB Understand the endocrinology control of adrenarche, pubarche and gonarche
Change in adrenal secretion
Zona reticularis develops as adrenarche occurs
Secretion of DHEA (pubarche)
Increases from 10 y.o. to mid 20s then declines through life
Sometimes acne
Causes
?Unknown molecular
Body weight
Leptin, insulin???
Normal remodelling
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What are pilosebaceous units?
*LOB Understand the endocrinology control of adrenarche, pubarche and gonarche
Sebaceous PSU
glands that secrete for hair
sudden increase of angrogens
over production of sebum
acne
Vellous PSU
Fine hair that cover body
Androgen exposure
develops for terminal PSU (beard)
develops for Apocrine (axillary and pubic hair)
scent glands
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is gonadarche?
*LOB Understand the endocrinology control of adrenarche, pubarche and gonarche
HPG first activated at 16wk until 1-2y.o
GnRH neurones are restrained until 10 y.o
Reactivated at Gonadarche
Rise in pulsative GnRH release
?????Kisspeptine role?????
Activation of gonadal steroid production
Production of viable gametes
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
How does Gondanarche effect body?
“Growth Spurt”
*LOB Understand the endocrinology control of adrenarche, pubarche and gonarche
Epiphysal Fusion
“Growth Spurt”
Ends of long bones
As oestrogen levels become higher you get epiphyseal fusion and growth stops.
Higher oestrogen in females so epiphyseal fusion occurs earlier- smaller height in women.
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What stimulates the onset of puberty?
*LOB Understand the endocrinology control of adrenarche, pubarche and gonarche
Theoretically…
Genetic: maturation of GnRH neurones, environmental/ genetic factors
Body fat/ Nutrition: earlier as nutrition improved, 17-18% fat and 22% to maintan menstrual cycle- link with leptin
Kisspeptin potential activates GnRH neurones
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is consonance?
*LOB Understand the concept of consonance
Progression of changes
Order of changes that happen remains the same
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is the Tanner scale?
*LOB Understand the Tanner stages of puberty and physical changes occurring during these 5 stages
Examining a patient
Uses shape and size of external genitals
Shape and size of breasts
Sexual Hair
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is central precocious puberty?
*LOB: Differentiate between central and peripheral cause of precocious puberty
GnRH- dependent (central)
Excess GnRH- idiopathic or secondary
Excess Gonadotrophin secretion- pituitary tumour
Maintains consonance
Accelerated linear growth, advanced bone ages, increased FSH, LH, estradiol and testosterone
Use GnRH analogues until later age
Surgery, radio or chemotherapy
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is peripheral precocious puberty?
*LOB: Differentiate between central and peripheral cause of precocious puberty
Testoxicosis activating mutation of LH receptor leading to early androgen production
No FSH (no spermatogenesis)
Causes
Sex steroid secreting tumour or exogenous steroids – secondary sexual characteristics
McCune Albright - constitutive activation of adenylyl cyclase - hyperactivity of signalling
pathways including those of gonadotrophin hormones.
Congenital adrenal hyperplasia – androgen production by the adrenal glands.
Hypothalamic-Pituitary-Gonadal Axis and Puberty by
What is pubertal delay?
*LOB: Recognise major causes of delayed puberty
More common in boys
Absence of secondary sex maturation by 14 yo (m), 13 yo (f) or absence of menarche by 18 yo
Constitutional Delay- secondary to chronic disease
Hypogonadotrophic hypogonadism - low LH, low FSH, low activation of gonads
Hypergonadortophic hypogonadism- high LH, high FSH, Klinefelter XXY, Turners, gonadal dysgenesis, mumps
Menopause and HRT M5 by Dr Judith Ibison
What is Menopausal transition?
*LOB: Define the menstrual transition and menopause in physiological terms
Period of time from changes in menstrual pattern to menopause
Menopause and HRT by Dr Judith Ibison
What is perimenopause?
*LOB: Define the menstrual transition and menopause in physiological terms
A period of changing ovarian function preceding menopause by 2-8 years
Not consistently defined
Menopause and HRT by Dr Judith Ibison
What is Menopause?
*LOB: Define the menstrual transition and menopause in physiological terms
Permenant cessation of menstruation due to loss of ovarian follicular function
Amenorrhoea for 12 months
Retrospective diagnosis (Think contraception)
Menopause and HRT by Dr Judith Ibison
What is premature ovarian failure?
*LOB: Define the menstrual transition and menopause in physiological terms
Menopause < 40 yo
Menopause and HRT by Dr Judith Ibison
What are the symptoms of menopause and why?
*LOB: Consider which symptoms can be ascribed to the menopause, and relate symptoms to what is known about the physiology
Sometimes none
Reduced cycle length- Reduced follicular phase
Some experience irregular periods with episodes of amenorrhea- why?
Year before: hot flushes, distrubed sleep -declining oestrogen
Dry Vagina -oestrogen declined
Impaired fertility
Menopause and HRT by Dr Judith Ibison
What physiology events lead to menopause
*LOB: Consider which symptoms can be ascribed to the menopause, and relate symptoms to what is known about the physiology
Reduced number of follicles per ovary
Due to increased cell death
Increased follicular recruitment
Reduced number and function of granulosa cells
Low AMH -> High FSH
Low Inhibin A and B -> High FSH
Reduced Oestrogen and Progesterone for survival factors for ovum
Fewer FSH receptors impair recruitment
Oocyte Function
Lack of growth factors / impaired from granulosa
Increased anueploidy
Impaired follicle recruitment
Anovulatory cycles and increased miscarriage rate.
Menopause and HRT by Dr Judith Ibison
What are cycle characteristics in menopause?
*LOB: *LOB: Consider which symptoms can be ascribed to the menopause, and relate symptoms to what is known about the physiology
Shortened Cycle (early MT)
Decline in inhibin B (granulosa)
Increased FSH in follicular
Early elevated oestrogen and early LH surge
Delayed/ Absent Ovulation (late MT)
Oestrogen early in cycle by high FSH but levels dont induce GnRH surge (impaired granulosa)
Ovularion delayed/ not occuring
FSH insensitivity due to fewer granulosa cell receptors
Heavier periods
Longer oestrogen stimulation of endometrium
Breast tenderness
Transitiory increases oestrogen for long time
Hot fluses
Low oestrogen -> serotonin disturbance, resets thermoregulatory nucleus
Menopause and HRT by Dr Judith Ibison
What are hormonal characteristics in menopause?
*LOB: *LOB: Consider which symptoms can be ascribed to the menopause, and relate symptoms to what is known about the physiology
AMH levels first show declining ovarian function
Inhibin B declines
FSH vary each cycle, increasing towards menopause
LH increases but later in menopause
Oestrogen falls close to menopause
No progesterone after menopause
Menopause and HRT by Dr Judith Ibison
Managing Menopause
*LOB: Outline the clinical management of menopausal symptoms
HRT
**Non-Hormonal ** incl clonidine, SSRI, SNRI, Gabapentin
Non Pharm Phytoestrogens (soya), Herbal (Black cohosh, St Johns Wort)
Behavioural CBT, Hypnotherapy
Menopause and HRT by Dr Judith Ibison
Prescribing HRT
Outline the clinical management of menopausal symptoms
60-80% efficacy reducing hot flushes
FHx Risk of cancer
**Progesterone use for 13 days with Uterus as protects against Endometrial Hyperplasia- 56% . **
Contraception if < 1 amennhorea
Low dose to avoid mastalgia, nausea,
Low risk for short term use,
Combined Oestrogen and Progesterone HRT
Continous combined or Cyclical Progesterone
Oestrogen Alone
Menopause and HRT by Dr Judith Ibison
Post menopausal therapy
*LOB: Describe the potential health benefits and harms of postmenopausal hormone therapy
- ??? Chronic disease prevention
- Licensed for menopausal symptoms only
- Increased risk of breast cancer and stroke/ thrombosis
- Alzheimers- NO RCT, no cognitive impact
- Worsening of prevalent incontinence and no change in incident incontinence with HRT
- Non-significant increase in ovarian carcinoma in users of combined HRT
- Oestrogens prevent osteoporosis just while being used
- Endometrial Hyperplasia- 56% . But protection with 10-13 days progesterone
- Gain in QoL from sleep, nil else
Menopause and HRT by Dr Judith Ibison
Fexolineant
*LOB: Outline the clinical management of menopausal symptoms
Fezolinetant is a non-hormonal neurokinin 3-receptor
antagonist that modulates neuronal activity in the
hypothalamic thermoregulatory centre.
◦ MHRA approved 2023
◦ Awaiting NICE appraisal so currently only pp.
◦ No long term data on safety
Menstrual Cycle by Dr Suman Rice
What are the aims of the menstrual cycle?
*LOB: List the aims of the menstrual cycle
- selection of a single oocyte
- correct number of chromosomes in eggs i.e. haploid
- regular spontaneous ovulation
- cyclical changes in the vagina, cervix and Fallopian tube
- preparation of the uterus
- support of the fertilised dividing egg
Menstrual Cycle by Dr Suman Rice
How is the menstrual cycle controlled?
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
Feedback loop between Hypothalamus, Ant Pituitary and the Ovary, led by GnRH, FSH/ LH, Oestrogen and Progesterone
Menstrual Cycle by Dr Suman Rice
Why is GnRH Pulsatile?
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
When GnRH is continuous, it causes levels of LH to drop due to desensitisation of the pituitary gland
Menstrual Cycle by Dr Suman Rice
What is the menstrual cycle?
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
Cyclical
2 Phases: follicular and luteal, seperated by ovulation.
In a 28 day cycle, day 1 is 1st day menses
Menstrual Cycle by Dr Suman Rice
What is the follicular phase?
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
Growth of antral follicles up to ovulation
Dominanted by oestradiol production from antral follicles
Approx 14 days.
Ends with Ovulation (middle of the cycle)
Menstrual Cycle by Dr Suman Rice
What is the Luteal Phase?
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
formation of corpus luteum from the remaining cells of follicle
dominated by progesterone production from corpus luteum
Occurs after Ovulation, Approx 14 days
Menstruation if no pregnancy
Menstrual Cycle by Dr Suman Rice
What is the HPO axis for Menstruation.
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
Luteal phase
Negative feedback by Progesterone
Follicular phase=variable
1. Release/removal of negative feedback
2. Negative feedback is reinstated, then
3. Switch from negative to positive feedback
Menstrual Cycle by Dr Suman Rice
What is the HPO Axis for
Late Luteal, Early Follicular
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
Menstrual Cycle by Dr Suman Rice
What is the HPO Axis for
Mid Follicular
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
Menstrual Cycle by Dr Suman Rice
What is the HPO Axis for
Mid Cycle
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
Menstrual Cycle by Dr Suman Rice
What is the HPO Axis for
Mid Luteal
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
Menstrual Cycle by Dr Suman Rice
LOOK COVER CHECK.
Assign the phases of the menstrual cycle to the HPO
*LOB: Describe the phases of the menstrual cycle and its endocrinological control
Menstrual Cycle by Dr Suman Rice
What is the Inter-cycle rise of FSH?
*LOB: Describe the processes of follicle selection, ovulation and formation of the corpus luteum
Raised FSH present a “window” of opportunity to recruit antral follicles that are at the right stage to continue growth
Oestradiol levels rise reinstating negative feedback at pituitary causing FSH levels to fall prevents further follicle growth
Menstrual Cycle by Dr Suman Rice
What is the FSH threshold Hypothesis for Dominant Follicle Selection?
*LOB: Describe the processes of follicle selection, ovulation and formation of the corpus luteum
- One follicle from the group of antral follicles in ovary is just at the right stage at the right time to survive declining FSH
- This becomes the dominant follicle which goes onto ovulate
- Known as “selection”
- Can be in either ovary
Menstrual Cycle by Dr Suman Rice
What happens to the DF as FSH falls?
*LOB: Describe the processes of follicle selection, ovulation and formation of the corpus luteum
LH increases
DF acquires LH receptors on granulosa cells
Other follicles do not, so they lose their stimulant and die
Menstrual Cycle by Dr Suman Rice
What triggers the Ovulation cascade?
*LOB: Describe the processes of follicle selection, ovulation and formation of the corpus luteum
If oestrogen levels are high enough long enough (threshold)
Triggers pituitary to start an LH rise
LH increase causes 3’ follicle to “pop’
Ovulation
Uterus, Uterine Tubes and Cervix by Dr David Gillott
Describe the Anatomy
*LOB: Describe the functional anatomy of the uterine tubes, uterus, cervix and vagina
Uterus, Uterine Tubes and Cervix by Dr David Gillott
How does the uterus and cervix change?
*LOB: Describe the functional anatomy of the uterine tubes, uterus, cervix and vagina
Maternal steroids increase size of new-born uterus.
Grows with height during infancy.
Myometrium dependent on estradiol.
Corpus of uterus undergoes greater increase in size than cervix.
Uterus, Uterine Tubes and Cervix by Dr David Gillott
What is the myometrium?
*LOB: Describe the functional anatomy of the uterine tubes, uterus, cervix and vagina
Outer muscular myometrium grows gradually throughout childhood.
Increases rapidly in size and configuration during puberty.
Changes in size through the cycle. Capable of vast expansion during pregnancy.
Inner layer circular fibres.
Middle layer figure of 8 or spiral fibres.
Outer layer longitudinal fibres.
Uterus, Uterine Tubes and Cervix by Dr David Gillott
What is the Endometrium?
*LOB: Describe the cyclical changes in female reproductive organs co-ordinated by the menstrual cycle
Very thin in childhood. Begins to thicken at puberty.
Dependent on steroids and responds cyclically to hormone changes.
Estrogen principally causes growth in proliferative phase. Can be seen and measured on an ultrasound scan. Good ‘bioassay’ of estradiol level…7-16mm.
Changes in glandular and epithelial cells through the cycle. Progesterone causes mainly differentiation in secretory phase.
At menstruation most of the endometrium is lost.
After menstruation - stromal matrix with small columnar cells with glandular extensions 2-3mm thick
glands are simple and straight.
Uterus, Uterine Tubes and Cervix by Dr David Gillott
What is the Endometrial proliferative phase?
*LOB: Describe the cyclical changes in female reproductive organs co-ordinated by the menstrual cycle
Proliferative phase (follicular phase of ovary) following menses. Stimulated by estrogen from the growing follicle.
Stromal cell division, ciliated surface. Glands expand and become tortuous, increased vascularity, neoangiogenesis. Maximal cell division by days 12-14.
When endometrium >4mm induction of progesterone receptors and small muscular contractions of the myometrium.
Uterus, Uterine Tubes and Cervix by Dr David Gillott
What is the Endometrial secretory phase?
*LOB: Describe the cyclical changes in female reproductive organs co-ordinated by the menstrual cycle
Secretory phase (luteal phase of ovary) 2-3 days after ovulation, the gradual rise in progesterone causes a reduction in cell division.
Glands increase in tortuosity and distend. Secretion of glycoproteins and lipids commences.
Oedema, increased vascular permeability, arterioles become increasingly convoluted to increase surface area.
Myometrial cells enlarge and blood supply increases.
Uterus, Uterine Tubes and Cervix by Dr David Gillott
Regression of the corpus luteum
*LOB: Describe the cyclical changes in female reproductive organs co-ordinated by the menstrual cycle
Corpus luteum stimulated by LH from pituitary during luteal phase.
The fertilised oocyte becomes a blastocyst and produces human chorionic gonadotrophin (hCG) which acts like LH (binds to LH receptor) and ‘rescues’ the corpus luteum.
In the absence of this, falling levels of steroid from the corpus luteum results in menstruation.
Uterus, Uterine Tubes and Cervix by Dr David Gillott
What is the Menstruation?
*LOB: Describe the cyclical changes in female reproductive organs co-ordinated by the menstrual cycle
Prostaglandin release causes constriction of spiral arterioles. Hypoxia causes necrosis.
Vessels then dilate and bleeding ensues.
Proteolytic enzymes released from the dying tissue.
Outer layer of endometrium shed, 50% lost in 24hrs, up to 80ml is considered normal. Bleeding normally lasts 4+ days.
Basal layer remains and is then covered by extension of glandular epithelium.
Estrogen from follicle in next follicular phase starts cycle off again.
Uterus, Uterine Tubes and Cervix by Dr David Gillott
Anatomy of the Uterine tube
*LOB: Describe the functional anatomy of the uterine tubes, uterus, cervix and vagina
Uterus, uterine tubes and cervix by Dr Gillott
Changes in cells lining the uterine tubes
Epithelial cells express high numbers of estrogen receptors & undergo differentiation in response to estradiol increase in height mid-cycle.
Oocyte can only pass down the tube during mid-cycle. Cilia beat and secretory cells are active along with muscle layer contractions, all in response to estrogen.
After a few days of exposure to progesterone the estrogen receptors are supressed and estrogen effects are overcome causing decrease in height mid-luteal onwards.
Uterus, uterine tubes and cervix by Dr Gillott
Cervix
*LOB: Describe the cyclical changes in female reproductive organs co-ordinated by the menstrual cycle
Muscular structure capable of great expansion.
The endocervical mucosa is about 3mm thick, lined with a single layer of columnar mucous cells, containing numerous tubular mucous glands which empty viscous alkaline mucus into the lumen.
Protective barrier to infection…
However, it has to allow passage of motile sperm.
The ectocervix is covered with nonkeratinized stratified squamous epithelium, resembling the squamous epithelium lining the vagina.
Folliculogenesis by Dr Suman Rice
How does the Primodrial Follicle form?
*LOB: Describe the formation of the follicle from primordial germ cells in utero, with an understanding of how mitosis and meiosis are involved in this
Each primary oocyte is surrounded by protective layers and cells
In foetal ovary, surrounding cells condense and diffx into Granulosa cells GC
The GC secrete acellular layer called Basal Lamina
This is the primordial follicle
Folliculogenesis by Dr Suman Rice
How does folliculogenesis occur?
*LOB: Describe the process of growth of follicles from the resting primordial follicle to ovulation of a mature oocyte and the time span of this process
- Puberty- cohort of follicles initiate growth each day
- Still Meiosis 1
- As follicles grow GC mutliple
- Oocyte secretes protective acellular layer Zona Pellucida
- A second layer of cells differentiate around the basal lamina forming the Theca (vascular)
- Gaps form in granulosa layer called Antrum, filled with Follicular fluid and these are called Secondary Follicles
Folliculogenesis by Dr Suman Rice
Antral Follicles
*LOB: Describe the process of growth of follicles from the resting primordial follicle to ovulation of a mature oocyte and the time span of this process
- Characterised by a cavity or “antrum”
*Contains fluid formed as exudate of plasma containing
secretory products of oocyte & GC
*Known as “follicular fluid”
*As follicular fluid volume and antrum expands, oocyte is
displace to one side - A cohort of early antral follicles will reach the right
stage and size that corresponds to the start of the intercycle rise in FSH. - These antral follicles continue growing.
- This is known as follicle recruitment
One will be selected for Ovulation
Folliculogenesis by Dr Suman Rice
What is the folliculogenesis timeline?
*LOB: Describe the process of growth of follicles from the resting primordial follicle to ovulation of a mature oocyte and the time span of this process
Folliculogenesis by Dr Suman Rice
The ovarian follicle produces steroids… how?
*LOB: Detail the production of steroids and the compartmentalisation of steroid enzymes in the follicle
Theca Cells have LH Receptors and no FHS Receptors
Granulosa cells have FHS Receptors and LHR (in midfollicular phase)
2 Cell 2 GnTrophin Theory
Theca cells via LHR convert Cholesterol
That converted molecule (androstenedione) is transported to Granulosa Cells
FSH receptors can convert to Estradiol
Folliculogenesis by Dr Suman Rice
Events before Ovulation
*LOB: List the events in the follicle and oocyte leading up to ovulation and fertilisation, including the mechanism of chromosome number reduction
- Follicle development begins with FSH stimulation.
- Oocyte maturation involves meiosis I until ovulation (M2)
- Ovulation is triggered by LH surge, releasing the oocyte.
- Fertilization occurs when sperm penetrates the oocyte.
- Chromosome number reduction happens during fertilization, where the secondary oocyte completes meiosis II.
Fertilisaation and the Luteal Phase by Dr D G
What is acrosome reaction?
*LOB: Describe the process of sperm capacitation and acrosome reaction
- Occurs in contact with the zona –cumulus complex
- the acrosomal membrane on the sperm head fuses releasing
- enzymes that cut through the complex.
- Acrosin bound to the inner acrosomal membrane digests the zona pellucida so the sperm can enter
ulipFertilisaation and the Luteal Phase by Dr D G
Stucture and Function of Oocyte at Ovulation
*LOB: Describe the process of fertilisation
Fertilisaation and the Luteal Phase by Dr D G
Sperm binding and penetration
*LOB: Describe the process of fertilisation
- The acrosome reaction occurs in contact with the zona-cumulus complex.
Sperm penetrate cumulus and bind to ZP. - Sperm enzymes cut through ZP, fuses w plasma membrane
- Sperm taken in by phagocytosis. Phospholipase Zeta activated by basal Ca2+ inside egg.
PIP2 → DAG + IP3
Causes release of intracellular
Ca2+ leading to large Ca2+ spike. - Cortical reaction as wave of Ca2+ sweeps around egg…release of proteases, peroxides and hyaline prevents polyspermy.
Fertilisaation and the Luteal Phase by Dr D G
What is syngamy?
*LOB: Describe the process of fertilisation
Entry of spark causesan increase Ca2+ in phospholipase Z from sperm
Cas2+ causes completion of meiosis 2 expelling polar body
Sperm nuclear membrane breaks down, chromatin decondenses and c.s separate
4-7 hours after sperm the two haploid c.s surrounded by membranes= pronuclei to synthesise DNA for mitosis
Pronuclei fuse
Mitosis occurs
Contraception by Dr Liza Bowen
Methods of Contraception
*LOB: Describe the modes of action of common methods of contraception
Contraception by Dr Liza Bowen
How does Fertility Awareness work?
*LOB: Describe the modes of action of common methods of contraception
- Predicting fertile window to avoid
- 7 days before ovulation and 1 day after
- Ovulation is 14 days before period.
- Monitor for 12 months first
- Basal body temp, cervical mucus consistency, urinary LH detection
- Failure rate 24% with typical use
Andorgen and antiandrogen
Characteristics of Nuclear Receptors
When these receptors bind steroid hormones
they are activated.
– Thus they are called ligand-activated receptors
– The binding of steroids to the ligand binding
domain causes a physical restructuring of the
polypeptide chains in the receptor, activating it
Androgen and Antiandrogen
Main steroid receptors
Androgen and antiandrogen
Dihydrotestosterone
Metabolism to the more potent agonist dihydrotestosterone
(DHT) by 5alpha-reductase enzymes in target cells, drives the
growth of the prostate, scrotum and phallus.
* Reduced androgen signalling in males can result in
undervirilization and infertility
Androgen and Antiandrogen
Effects of testosterone and DHT on secondary characteristics in males and female
Androgen and antiandrogen
Androgens in females
Androgen and antiandrogen
How are androgens converted?
Androgen and antiandrogen
Androgen Insensitivity Syndrome
(AIS)
Genetically male, (XY). Are unable to respond to androgens, they may have mostly
female external sex characteristics or signs of both male and female sexual
development.
Adverse effects of anabolic androgenic steroids
Inhibition of Testosterone Conversion to DHT
Testosterone is converted in the prostate to a more potent androgen –
dihydrotestosterone – which drives prostate growth and function
Maternal Changes in Pregnancy by Dr Gillott
Early Implantation
*LOB: Describe the normal physiological changes in pregnancy
Decidual cells on surface of endometrium become filled with lipids and glycogen- becomes maternal part of the placenta.
The syncytiotrophoblast results from cell fusion (forms a multi-nucleated cytoplasmic mass) and invades the endometrium.
Chorionic gonadotropin is an autocrine
growth factor for the blastocyst.
Maternal Changes in Pregnancy by Dr Gillott
Implantation
*LOB: Describe the normal physiological changes in pregnancy
Implanting day 7-8
Syncytiotrophoblast erodes the
endometrium. Cells of the
embryonic disc form epiblast and
hypoblast. Epiblast develops fluid
filled amniotic cavity.
12-day blastocyst
Implantation complete as extraembryonic mesoderm forms discrete layer beneath
cytotrophoblast.
16-day embryo
Cytotrophoblast and associated mesoderm have become the chorion and chorionic villi are extending. Lacunae filled with maternal blood mingle with villi.
Maternal Changes in Pregnancy by Dr Gillott
Hormones in Pregnancy
*LOB: Describe the normal physiological changes in pregnancy
Serum hCG maximal by 9 – 11 weeks.
Estrogen and progesterone continue to rise as corpus luteum still produces steroids
Maternal Changes in Pregnancy by Dr Gillott
Glucose
*LOB: Describe the normal physiological changes in pregnancy
- Maternal Store (increased pancreatic cells and insulin)
- Foetal Store (Placental lactogen)
- Transfer to foetus
Maternal Changes in Pregnancy by Dr Gillott
Increased O2 consumption
*LOB: Describe the normal physiological changes in pregnancy
Maternal Changes in Pregnancy by Dr Gillott
Maternal Blood
*LOB: Describe the normal physiological changes in pregnancy
- Increased efficiency of iron absorption from gut.
- Circulating volume increases from 4.5 to 6.0 litres.
- Haemodilution - apparent anaemia as concentration of Hb falls.
- Increase in white cells and clotting factors, blood becomes hypercoagulable.
- Increased fibrinogen for placental separation, but increased risk of thrombosis.
Maternal Changes in Pregnancy by Dr Gillott
GI Tract
*LOB: Describe the normal physiological changes in pregnancy
Folic Acid supplementation
Maternal Changes in Pregnancy by Dr Gillott
Urinary System
*LOB: Describe the normal physiological changes in pregnancy
Maternal Changes in Pregnancy by Dr Gillott
Cortisol & placental CRH
*LOB: Describe the normal physiological changes in pregnancy
CRH released into maternal and foetal circulation by placenta. Increases cortisol (positive feedback) and stimulates adrenocorticotrophic hormone (ACTH) & so DHEA in foetal HPA axis
DHEA is aromatized into estrogen by the placenta.
Increasing E:P ratio snd stimulating prostaglandins which activate blood flow, uterine contractions & cervical ripening.
Maternal Changes in Pregnancy by Dr Gillott
Thyroid gland
*LOB: Describe the normal physiological changes in pregnancy
Increased production of thyroid hormone to meet increased metabolic demand of pregnancy leads to a risk of gestational thyrotoxicosis
hCG may act on TSH receptor.
Suppressed TSH and high serum T4 may indicate gestational thyrotoxicosis.
Maternal Changes in Pregnancy by Dr Gillott
Changes in cervix
*LOB: Describe the normal physiological changes in pregnancy
- Primary function is to retain the pregnancy
- Increase in vascularity
- Tissue softens from 8 weeks
- changes in connective tissue
- begins gradual preparation for expansion
- Proliferation of glands
- mucosal layer becomes half of mass
- great increase in mucus production
- Protective ie anti-infective
Maternal Changes in Pregnancy by Dr Gillott
Prolactin
*LOB: Describe the normal physiological changes in pregnancy
Prolactin
* produced by myometrium and placenta
* in response to high estrogen and progesterone.
* However, estrogen and progesterone inhibit the stimulatory effects of prolactin on milk production.
* The abrupt drop in estrogen and progesterone levels following placental delivery allows high levels of prolactin to induce lactation.
* After birth, sucking activates nipple mechanoreceptors signaling the hypothalamus and causing anterior pituitary prolactin secretion.
Maternal Changes in Pregnancy by Dr Gillott
Oxytocin
*LOB: Describe the normal physiological changes in pregnancy
Oxytocin
* Stretching of uterus and cervix during childbirth causes release of oxytocin
* which helps with the birth and emotional bonding with the baby.
* Suckling stimulus triggers the release of oxytocin from the posterior pituitary gland, which triggers milk ejection.
*
Pharmacology of Uterus by Antony Albert
Structure of Myometrium
*LOB: Outline the structure and function of the myometrium and the role played by interstitial cells of Cajal and smooth muscle cells
Outer longitudinal fibres
Middle figure of eight shaped fibres
Inner circular fibres
All smooth muscle
When contraction causes increases in uterine pressure forcing contents to cervix
Acts as a natural ligature to prevent blood loss
Pharmacology of Uterus by Antony Albert
Electrical and Mechanical Activity
*LOB: Outline the structure and function of the myometrium and the role played by interstitial cells of Cajal and smooth muscle cells
Slow waves:
slow depolarisations produced by pacemaker cells (ICCs)
Electrical activity spreads via gap junctions to SMCs
Activates action potentials in SMCs - upstroke of APs are carried by Ca2+ through VGCCs which leads to increase in [Ca2+]i AND contraction
Slow waves/SMCs are modulated by neurotransmitters /hormones
Pharmacology of Uterus by Antony Albert
Principles of Excitation and Inhibition
*LOB: Outline the structure and function of the myometrium and the role played by interstitial cells of Cajal and smooth muscle cells
Spermatogenesis by Dr Gillott
Sertoli cells, tight junctions & adluminal compartment
Primary germ cells or spermatogonia on
the basement membrane
Walls of tubule made up of tall columnar
endothelial cells Sertoli cells. Tight
junctions between these form Adluminal
compartment.
Allows specific enclosed environment for
spermatogenesis which is filled with
secretions from Sertoli cells.
Spaces between the tubules are filled with
blood and lymphatic vessels, Leydig cells
and interstitial fluid.
Sperm stages during spermatogenesis
Spermatogenesis
Gonadotrophins act on the testis
Leydig cells contain LH receptors and primarily
convert cholesterol into androgens. Intra-
testicular testosterone levels are 100x those in
plasma.
Androgens cross over to and stimulate Sertoli
cell function and thereby control
spermatogenesis.
Sertoli cells contain FSH receptors and converts
androgens to oestrogen.
FSH establishes a quantitatively normal Sertoli
cell population, whereas androgen initiates and
maintains sperm production.
Erection and ejaculation
Semen analysis
Sperm morphology
Spermatozoon
Detail the process of steroid production in the male including its endocrinological control
