Gonadal steroidogenesis Flashcards
Where are the two areas in the body that steroid hormones are produced from cholesterol?
Adrenal glands and gonads
What is the HPG axis?
Hypothalamic-pituitary-gonadal axis
Hypothalamus secretes Gonadotropin-releasing hormone (GnRH) which stimulates the pituitary to release LH and FSH
This causes the testis to produce testosterone and the ovaries to produce estrogen and progesterone
How the HPG axis activity change throughout the individuals life?
What is testosterone required for?
Testosterone is required for spermatogenesis (sperm production) and important for development of primary and secondary sexual characteristics, increasing libido and increasing bone and muscle growth
What are leydig and Sertoli cells?
Leydig cells= produce testosterone
Sertoli cells= produce sperm
Both present in testis
What is the feedback pathway in the HPG axis for males?
What do sertoli cells get stimulated by, and what do they produce?
Stimulated by FSH to produce inhibin and activin which have both negative and positive feedback loops
Also produce sperm
What stimulates leydig cells, and what do they produce?
LH stimulates leydig cells to produce testosterone
How do the testosterone levels affect what the Sertoli cells produce?
Raised testosterone levels= increases inhibin, low testosterone levels= activin
What is a oocyte?
In the ovaries, there are follicles each containing an egg- known as a oocyte.
A single oocyte will be released from the dominant (largest) follicle during each menstrual cycle
What cells are within follicles?
Theca cells
Granulosa cells
What does FSH act on and what are the effects? (female)
FHS acts on granulosa cells to produce estradiol which stimulates preovulatory growth and granulosa cells also produce inhibins- only negatively feedback onto FSH
What is the feedback and forward pathways of the HPG axis in females?
How do the levels of estradiol change in the follicle as it matures?
As follicle grows, level of estradiol increased.
Once follicle has grown and ready to rupture, is secreting high levels of estradiol.
What are the feedback pathways of estradiol?
Moderate levels= negative feedback
High levels (in the absence of progesterone)= positive feedback, causing LH to be released and the LH spike causes egg to be released
What does LH act upon? (female)
LH surge when estradiol levels rise causes egg to be released
LH binds to corpus luteum and acts on theca cells to produce androgens and progesterone
What happens to androgens released by the corpus luteum?
converted to estradiol in granulosa cells
What type of feedback does high estradiol with progesterone give?
Negative feedback
When are hormones important for male development?
Hormones needed for development of testicular and reproductive systems in foetal life
Also important in puberty spermatogenesis and sperm production/ erectile function
What is needed for creation of testis and mascualisation of the foetus?
X,Y chromosomes result in the formation of testis
Testosterone needed in the mascuilisation of the foetus
How does regression of the female reproductive tract occur in male foetuses?
Anti-mullerian hormone (AMH) is produced by testicular sertoli cells and induces regression of mullein ducts
How does the amount of testosterone produced relate to the phenotype of geniltalia produced?
What enzyme converts testosterone to dihydrotestosterone?
5-alpha reductase
What receptor do testosterone and dihydrotestosterone act through?
Androgen receptor
What is the hormone pathway that affects gonadal descent and external geniltalia?
What is cryptorchidism?
Cryptorchidism is the absence of at least one testicle from the scrotum.
When is the HPG axis active in males?
During foetal development, then quiescent at birth and reactivated very shortly after birth in ‘mini puberty’
The HPG axis is inactive in childhood until puberty, then reactivated in puberty between 9-14 years
What is pubertal staging?
Tanner staging also known as Sexual Maturity Rating (SMR), is an objective classification system that providers use to document and track the development and sequence of secondary sex characteristics of children during puberty
What is the device used to measure testicular volume called?
Orchidometer
What are the different sizes of testicles throughout the life?
Red= pre pubertal
Blue= Pubertal
Green= adult
What are the two conditions associated with hormone imbalance in the testis?
Hypogonadotrophic hypogonadism
Hypergonadotrophic hypogonadism
What is hypogonadotrophic hypogonadism?
- Abnormalities with production of gonadotrophins in brain
- LH , FSH and testosterone low
- symptoms are delayed puberty
What is hypergonadotrophic hypogonadism? (male)
- High LH and FSH but low testosterone
- Problem in the testis
What are causes of hypergonadotrophic hypogonadism? (male)
Klinefelter syndrome, chemo or radiotherapy and abnormal dysgenesis (abnormal development)
What is Klinefelter syndrome?
Klinefelter syndrome is where boys and men are born with an extra X chromosome.
Klinefelter syndrome may adversely affect testicular growth, resulting in smaller than normal testicles, which can lead to lower production of testosterone.
What are the systemic effects of testosterone?
Brain= libido and aggression
Skin- hair growth, balding
Muscle- increase in strength and volume
Bone- accelerated linear growth, closure of epiphyses
Male sexual organs- penile growth, prostate growth/function and spermatogenesis
What is hypospadias?
Hypospadias is a birth defect in boys in which the opening of the urethra is not located at the tip of the penis
The abnormal opening can form anywhere from just below the end of the penis to the scrotum.
What are the causes of testicular dsygenesis syndrome?
Environment
What are the different types of testicular dysgenesis syndrome?
Cryptorchidism, hypospadias
Infertility, tesicular cancer and hypogonadism
What is the main cause of disorders of sex development?
Genetics
What are the main disorders of sex development?
Ambiguous geniltalia
Gonadal tumours
Hypogonadism
Infertility
What tests would a doctor have done on a baby with ambiguous geniltalia?
- Determine genetic sex by getting a blood test and look at chromosome
- Determine what the gonads and the internal reproductive structures are via ultrasound or MRI
- Check hormone activity
- Check receptors for mutations if there is abnormal hormone activity
What are babies with XX or XY chromosomes and ambiguous genitalia referred to as?
XY= undervirilised male
XX= virilised female
What are the 3 different hormonal problems that could arise in a male with ambiguous geniltalia?
problem with testosterone, problem with conversion of testosterone to DHT or the androgen receptor
What is partial androgen sensitivity syndrome?
Partial androgen insensitivity syndrome (PAIS) is a genetic (inherited) condition that occurs when the body can’t respond to male sex hormones (androgens). Testosterone is a male sex hormone.
Can be complete insensitive
What cancer treatment can affect the gonadal function?
Chemotherapy and radiotherapy
Can affect testosterone levels from pituitary, or directly damage gonads
At what stage of testicular volume is the highest height growth velocity occurring?
10 mils
What is the genetic version of hypogonadotrophic hypogonadism called?
congenital hypogonadotrophic hypogonadism
What are causes of hypogonadotrophic hypogonadism? (male)
Genetic
Idiopathic
Kallmann syndrome
What is Kallmann syndrome?
Kallmann syndrome combines an impaired sense of smell with a hormonal disorder that delays or prevents puberty.
How do you check for testicular cancer?
Imaging, biochemistry (hCG, AFP and LDH)
What are the differences in numbers of sperm and eggs?
Men- constant fertility from puberty, 300 million sperm a day. Gradual decline with age
Women- cyclical fertility, 3-5 days a month. There is 7 million follicles in utero, declines to 0 at menopause
Around 400 follicles are ovulated
What is the function of estradiol?
Type of oestrogen, regulates:
- Endometrial proliferation during menstrual cycle
- Female genital development
- Secondary female sex characteristics e.g. breast development, body fat distribution, bone (epiphyseal closure)
Lack of what hormone can cause an increased risk of osteoporosis after the menopause?
Oestrogen
What does progesterone regulate?
- Endometrial secretion and vascularisation during menstrual cycle (prepare uterus for pregnancy)
- Maintain pregnancy and support embryo
How does hormonal contraception work?
Manipulation of steroid gonadal hormones, suppresses ovulation via negative feedback of progesterone
Oestrogen in combined pill provides additional feedback and promotes progesterone receptor expression
Also has secondary effects on female genital tract-makes uterus environment less hospitable
What are the different hormone levels throughout the cycle?
What is normal length of a menstrual cycle?
24-35 days for a cycle
What stage of follicle growth do gonadotrophin regulate?
Later stages of follicle growth
What is produced by growing follicles to inhibit growth of smaller follicles?
Anti-mullerian hormone by the granulosa cells
How does the hormonal change occur upto the follicle release in menstrual cycle?
Rise in FSH levels cause a rise in estradiol levels which is made in follicles and causes endometrium to thicken
Estrogen is produced in higher levels as the follicle grows, stimulates LH to be produced and swaps to positively feedback onto FSH
LH surge causes follicle to be released
Does rise in oestrogen negatively or positively feedback onto FSH?
Initially, rise of oestrogen negatively feedbacks onto FSH, which ensures there is only one follicle per month
At a certain threshold, its effect reverses and it now has a positive effect on FSH secretion
What does FSH do?
Stimulates the growth of eggs in the ovary
What happens to the levels of estradiol as follicle is released?
It drops, however still some being produced by the corpus luteum
What happens to the follicle after the oocyte has been released from the ovaries?
Becomes the corpus luteum
Produces progesterone
What is Luteinisation?
The process by which elements of the ovarian follicle, usually including both theca interna and granulosa cells, are provoked by the ovulatory stimulus to develop into the corpus luteum.
What causes the corpus luteum to regress?
If there is no pregnancy, the embryo does not produce hCG so the corpus luteum does not receive any signals to indicate it should keep producing progesterone
What happens when the corpus luteum regresses?
There is a drop in progesterone and estradiol as it is no longer producing these
This feedsback to the anterior pituitary and FSH starts to rise again
The endometrium is shed
What happens to the corpus luteum if implantation occurs?
If implantation does take place, blastocyst produces hCG, which is structurally similar to LH. Binds to LH receptors on CL to provide the blastocyst with the progesterone that it needs until the placenta is well enough established
What hormone encourages the corpus luteum to produce progesterone?
hCG and LH
What are the two hormones involved in lactation and where are they released from?
Prolactin- anterior pituitary
Oxytocin- posterior pituitary
What stimulates the release of prolactin and oxytocin and what is their function
Sucking sends nerve impulses to the brain, which causes the release of these
Prolactin- causes alveoli in breasts to swell and secrete milk
Oxytocin- acts upon the myoepithelial cells around the alveoli causing milk expulsion, also may have an effect on uterine smooth muscle to include labour
What are the two phases of the endometrium before shedding?
How is estradiol created?
Cholesterol is covered to androgen in the theca cells
Androgen is converted to estradiol in granulosa cells
What would be the problem with low LH, FSH, estradiol and normal prolactin in someone with irregular periods?
Problem with hypothalamus, GnRH would be low
Brain can switch off HPG when they have low body fat due to anorexia or too much exercise, or chronic illness or stress
Known as hypogonadotrophic hypogonadism
What would be the problem with high LH and FSH, low estradiol and normal prolactin?
Ovary is problem
May be due to Turner syndrome or premature ovarian insufficiency, happens naturally in menopause
What is atrophic vaginitis and what can cause it?
Vaginal atrophy (atrophic vaginitis) is thinning, drying and inflammation of the vaginal walls that may occur when your body has less estrogen
What is Turner’s syndrome?
Turner syndrome, a condition that affects only females, results when one of the X chromosomes (sex chromosomes) is missing or partially missing.
Can lead to early menopause, even sometimes menopause before puberty
What is premature ovarian insufficiency?
Primary ovarian insufficiency occurs when the ovaries stop functioning as they should before age 40. When this happens, your ovaries don’t produce typical amounts of the hormone estrogen or release eggs regularly
What is the problem when LH, FSH and estradiol are all low, however there is high prolactin, and periods are irregular?
Problem in the pituitary, mimicking the hormones of breastfeeding
When prolactin is high, pituitary switches off reproduction hormones because you don’t want to be pregnant whilst supposedly breast feeding.
Can have a small prolactin secreting tumour
May present with galactorrhoea, a milky nipple discharge
What is the problem when LH is high, and estradiol, FSH and prolactin are normal but there is irregular periods?
Polycystic ovaries can be a cause of this- Andorgen pauses growth of large follicles but not smaller ones so the follicles will grow- then pause and there will be an ovary with lots of paused eggs in them
What is polycystic ovary syndrome?
Women with PCOS produce higher-than-normal amounts of male hormones (androgens)
This causes hirsuitism (excessive growth or dark hair), acne, weight as well as irregular periods
What is oligomenorrhoea?
Oligomenorrhoea= period abscence in > 42 days
What is amenorrhoea?
Amenorrhoea= period absence > 6 months, can be primary (never had a period) or secondary (the periods stopped)
What is an anvolatory cycle and what can cause it?
An anovulatory cycle is a menstrual cycle in which ovulation, or the release of an egg from the ovaries, does not occur. Anovulation is often due to hormonal imbalances that can be the result of using hormonal birth control, being underweight or overweight, exercising excessively, or experiencing significant stress
What are the 4 reasons a patient may not get a period?
- Pregnancy
- The ovary is running out of eggs- high levels of LH and FSH. Premature ovarian insufficiency
- The hormone signals are low, low LH and FSH, happens naturally after menopause, before puberty or breastfeeding
- Hormones are giving mixed messages to the ovary
What will the hormonal levels be in someone with premature ovarian insufficiency?
What are the causes of premature ovarian syndrome?
Can be an autoimmune condition, or genetic (usually problem with x chromosome, such as Turner’s syndrome)
Could be infection or iatrogenic due to cancer treatment
What does a high level of anti-mullerian hormone mean?
Large number of follicles
What will hormone levels look like in hpogonadotrophic hypogonadism in females?
What can switch off and impact prolactin positively?
Dopamine= switches off prolactin
TRH= affect prolactin positively
Drugs that are dopamine antagonists may raise prolactin e.g. anti-psychotics
What will hormone levels look like in a female with hyperprolactinaemia (high levels of prolactin)?
What will hormone levels be like in a patient with polycystic ovary syndrome?
What medication should patients with POS take when trying to get pregnant and when should they take it?
For pregnancy, used letrozole (estrogen blockers), but only give for 5 days at the start of the month, as oestrogen is needed later in the cycle
How does the increasing levels of estradiol effect the cervical mucus?
Thins the cervical mucus- allows for easier passage of sperm
What is decidualisation?
Decidualization refers to the functional and morphological changes that occur within the endometrium to form the decidual lining into which the blastocyst implants.
There is an acute inflammatory response in the endometrium, and massive NK cell proliferation during decidualisation
What can disturbance of endometrial receptivity and disidualisation cause?
Can cause endometrial functional inadequacy
Can lead to implantation failure, recurrent miscarriage, pre-eclampsia (high blood pressure during pregnancy)
What is endometriosis?
Characterised by the growth of endometrial tissue outside of the uterus
Associated with chronic pain, inflammation and infertility
What is endometriosis thought to be caused by?
Thought to be caused by retrograde menstruation; backwards efflux of menstrual debris through the fallopian tubes and into the pelvic cavity
What do the majority of breast cancer start out as?
Oestrogen dependant cancers
What are the causes and risk factors of endometrial cancer?
- Estrogen (and insulin) in excess and lack of progesterone affect endometrial proliferation and cell survival
- Results in increasing the risk of epithelial cell transformation/carcinogenesis
- Risk factors= excess fat, older forms of HRT and some forms of breast cancer treatment
What hormones are good/bad in breast, ovarian and endometrial cancer?
Estrogen= increases proliferation/oncogenes, decreases apoptosis and tumour suppressors (bad)
Progesterone= represses estrogen dependant genes, increases apoptosis and reduces cell cycle-and proliferation (good)
What can estrogen over expression lead to?
Cancerous lesions or autoimmune conditions
What are some risks of excess oestrogen?
Depression, irritability and mood swings
Fluid retention
Headaches
Poor sleep
Fatigue
Weight gain
Increases risk of cancerous lesions or auto immune diseases
What different biological processes does estrogen help with? (Not including gonadal processes)
- Helps to maintain body temperature
- Helps against memory loss
- Regulates production of cholesterol
- Helps to preserve bone density
In what scenarios are oestrogen agonists and antagonists used?
Used in HRT and the combined oral contraceptive pill
Oestrogen antagonist used in ovulation induction and breast cancer treatment
When are progesterone agonists and antagonists used?
Agonist- for menstrual induction and contraception
Antagonists are used for termination of pregnancy
What are some possible causes in people with amenorrhoea with high LH?
. Premature ovarian failure (insufficiency)
2. Polycystic ovary syndrome
3. Ovulation (endometrial problem -Asherman’s syndrome)
4. Gonadotroph tumour
What is Asherman’s syndrome?
Asherman’s syndrome is a rare condition where scar tissue, also called adhesions or intrauterine adhesions, builds up inside your uterus. This extra tissue creates less space inside your uterus
It can cause you to lose your period
What are some possible causes of high testosterone?
. Polycystic ovary syndrome
2. Congenital adrenal hyperplasia (late onset)
3. Androgen secreting tumour (ovary / adrenal)
4. Exogenous administration
What are some causes of low oestrogen?
Hypogonadotrophic hypogonadism
2. Hyperprolactinaemia
3. Premature ovarian failure (insufficiency)
4. Exogenous hormones (post Depo-Provera, contraception injection)
