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Year 3 > Science of repro > Flashcards

Science of repro Flashcards

1
Q

State the WHO (2021) criteria for semen analysis.

A
  • Sperm parameters are analysed which includes volume, liquefaction, appearance, conc, motility, morphology, vitality, pH and leucocyte
  • Volume- 1.4-6ml
  • Colour- grey-opalcencent
  • Liquafaction- under 30 min
  • Sperm conc- more than 16 million per ml
  • Motility- more than 42%
  • Morphology – more than 4 %
  • Vitality (live)- more than 54%
  • Ph- 7.2-8.0
  • Leucocyte- less than 1 million per ml
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2
Q

Identify the laboratory methods used in analysing sperm parameters (WHO, 2021).

A
  • Appearance and liquefaction- observation of a grey-opalescent colour and time taken should be 20-30 minutes
  • Volume- either direct volume measurement or volume from weight
  • Concentration- Measured using counting chamber and measured in millions per ml
  • Motility- assessed asap after liquefaction ,Mix the sample well, remove aliquots asap after mixing , make a wet prep pprox.. 20um deep and wait for sample to stop drifting. Then examine the slide with phase contrast optics at x200 or x400 magn. Assess pprox.. 200 spermatozoa in a total of at least 5 fields per replicate ( need 2 replicates per analysis)
  • Morphology-assess directly on the wet prep using and using stains
  • Vitality -asses the membrane integrity of the spermatozoa either dye exclusion#9 damaged cells allow membrane impermeant stains or hypo osmotic swelling test (only live cells will swell in hypnotic solutions
  • PH-asses asap after liquefaction
  • Leucocyte- round cells assessed using counting chamber and immunocytochemical staining
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3
Q

Understand the clinical significance of the different sperm parameters

A
  • Conc- below ref value – oligozoospermia
  • Motility- below- astenozoospermia
  • Morphology- below- teratozoopermia
  • Vitality- below necrozoospermia
  • Liquefaction - long liquefaction indicative of an infection
  • Leucocyte- increased number indicative of infection
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4
Q

Understand how follicles are formed and the ovarian reserve is established

A
  • 3-4 weeks ( epiblast cell in yolk sac at base of allantois differentiate into PGC
  • 5-6 weeks Mitotically dividing pgcs migrate along dorsal mysentry of hind gut to colonise genital ridge
  • Approx. 5-12 weeks germ cell cyst is formed with a cytoplasmic bridge between the mitotically diving oocyte called syncitia ( role? To exchange organelles )
  • Syncitia breakdown and somatic cells invade to surround oogonia to form PF
  • At this time many dies off
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5
Q

Appreciate the difficulties and techniques used to investigate folliculogenesis

A
  • Animal models – majority are poly-ovulatory and the some are mono but are too large and can be harder to maintain like cows compared to rats.Monkeys would be ideal but ethical issues
  • genotype/phenotype assosication in either naturally occurring mutations or knock- out mice.
  • Culture of whole ovaries/ slices/ biopsies/ large or small follicles/cells – but very difficult in human due to limited supply of tissue and primary cells difficult to obtain
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6
Q

Become aware of the current thinking about primordial follicle initiation

A
  • PF are in avascular ovarian cortex
  • oocyte surrounded by a single flattened layer of granuloses cells (Primordial stage)
  • changes from flattened to cuboidal (transitional stage)
  • single cuboidal layer of GC (Primary stage)
  • then acquires another layer of GC (Secondary stage)
  • start to get theca formation -formation of zona pellucid -Basement membrane
  • Intracelluar communication between oocyte and GC vis gap junction that penetrate ZP
  • Also communication via connexins ie. Cx43 between GC and Cx 37 between GC and oocyte
  • Initiation is caused by 2 main ideas
  • 1st idea- regulated by loss of an inhibitor
  • 2nd idea- regulated by stimulatory factors
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7
Q

Gain an understanding of some of the genes controlling pre-antral follicle growth at all stages

A

• Endocrine disruptors BP A, Genistein, DES inhibits nest breakdown
Nest breakdown ~7 primordial follicle assembly
• FIGLA
• Zona Pellucida 1-4
• Activin beta A &BDNF
• AMH
• Oestrogen
Primoridal Follicle activation
• KIT ligand and Ckit (KIT lingand is prodcued in the gc and wil bind to its receptor cKIT and activate PI3K which mediates the conversion of PIP2 to PIP3 which phosphorylates AKT and taht phosphrylates FOXO3 the FOXO-P then relaes cyclin d2 and cell cycle us activated again )
• FOXL2
• NOBOX
• SOHLH 1&2
Primordial Repression
• PTEN (PTEN inhibits by preventing AKT formation)
• FOXO3 (Transcription factor fOXO3 binds to cycline d2 and keep the cell in arrest int he dna preventing it from enterign the cell cycle)
• AMH from surrounding follicles and inhibits
• SDF-1 from surrounding stroma to inhibit

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8
Q

• Describe the structure and formation of an antral follicle

A

• Theca is crucial, theca is envelope of connective tissue which differentiate into theca interna and externa contain vascular tissue, immune cells and matrix factors
• Crucial in mainting struicturure and delivery of nutrient to avascukar gc layer
• When the follicle reach a diameter of 200-400um surrounder by vascularised theca it is subject to infuclences
• Fluid filled spaces appear between the gc cells which coalesce togthee to form a single, large fluid filled cavoty known as antrum
• The fuild comes from te plasm leakge from the cappilaries and contains secretory products of oocyte and gc too..it is known as follicular fluid
Structure
• Theca externa – concentrically arranged sm cells innervated by autonomic nerves and contains lympatic vessels
• Theca interna – steroid producing cells, contains LHr and insulin- r and richly vascularised
• Basal lamina
• Granulosa cells (mural)- involved in endocrine feedback control, express FSHr, p450arom and LHr
• Cumulus granulosa cells-remain in contact with oocyte and interact with oocyte by gap junction , mitotically active and NO LHr
• Zona pellucida
• Antrum
• Oocyte

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9
Q

• Understand the role that both FSH and LH have on antral follicle growth and function

A

Role of FSH
• Increase GC proliferation
• Increase aromatase
• Induce and mainting FSHr
• Induce and maintain LHr
• Interact with paracrine factors e.g androgens
Role of LH
• Increase theca function of CYP11a CYP 17
• Increase grown & steroidogenesis in dominant follicle
• Withdrawal of gap junctions between gc & oocyte and resumption of meiosis
• Expansion coc
• Ovulation and luteinisation
Fsh produce low cAMP and LH produces high cAMP

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10
Q

• Be aware of the clinical utility of AFC in assessing ovarian reserve and fertility.

A
  • Use ultrasound to count number of 2-8mm follicles at start of cycle and correlate to approximate the AMH serum levels
  • Low number of antral follicles are a sign of ovarian ageing
  • 3d printed ovary – from microporouds hydrogel scaffolds , the follicles seed ed through out to crate a mouse bio prostestic ovary- it provides a 3d support to follicles allowing for vascualrisation and ovulation
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11
Q

• Understand the diagnostic criteria for PCOS and its importance

A

• Diagnosis of exclusion (disorders that mimics pcos)
o Non-Classical adrenal hyperplasia
o Hyperprolactinemia, thyroid disease, cushing s syndrome
o Ovarian hyperthecosis
• Rotterdam criteria
o Need to have 2 out of 3
o 1) polycystic ovaries -either 12 or more antral follicles measuring 2-9 mm diameterand or increased ovarian volume more than 10 ml
o 2)Hyper-androgenism – either clinical oe biomechemical evidence
o 3)Ovulatory dysfunction -oligomennorhea/ anovulation

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12
Q

• Explain the prevalence in the population and possible genetic links(pcos

A
  • Very common and can present in different symptoms
  • Its present 87% with oligomenorrhoea
  • 87% with hirsutism and regular cyles
  • Most common cause of anovulatory infertitlity
  • Family aggregation
  • Monozygotic twins twice likely to both have pcos than dizygotic
  • Complex polygenic disease
  • 3 loci linked and candiate genes within this were LHCGR,FSHR,THADA and DENND1A in a gwas study
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13
Q

• Describe the complex endocrine disturbances that occur in PCOS and how this differs from the normal menstrual cycle

A
  • Elevated Lh
  • Low FSH
  • Rapid GnRh frq- favouring Lh pulse secretion
  • High testosterone impairs negative feedback by progesterone
  • They also have insulin resistance so there is ahigh level of insulin which acts as a co gonadotrophin with LH (binds to its own receptor but stimulates similar downdtream signalling pathway and merges with that of LH)
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14
Q

• Be aware of current hypotheses regarding the origin of PCOS

A
  • At same given weight women with pcos will have lower insulin sensitivity than a normal women
  • No mutation in insulin recpeot gene found in PCOS so could be due to post-recepto binding defect- somehwwere in the signalling pathway
  • 30-40% women with pcos have impaired glucose tolerance and 10% develop T2DM by age 40 yrs
  • Obesity &insulin resistace results in increased incidence of GDM
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15
Q

• Be aware of the life-long burden that PCOS has on the health of women

A
  • Obesity
  • Hypertension
  • Altedred lipid profile- high LDL and low HDL
  • Increase risk for the atherosclerosis disease
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16
Q

• Familiarise themselves with the myriad treatments on offer to alleviated the symptoms associated with PCO

A
  • First line management for menstrual abnormalities and hirsutism/acne in PCOS are hormonal contraceptives (HC)
  • First line therapy for infertility is clomiphene
  • Metformin – metabolic/glycaemic abnormalities & for improving menstrual irregularities
  • Tretinoin for hyperpigmentation
  • Hirsutism-COCP with non-androgenic progesterone , GnRH therapy (very severe cases), Weight reduction, Physical therapies-electrolysis, laser hair removal,shaving etc..
  • Infertitliy- clomiphene citrate, metformin+cc, aromatase inhibitor, ovarian puncture , IVF
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17
Q

• Understand the main causes of sub-fertility in the context of the male and female reproductive systems

A
  • Infection or occlusion of vas def or uterine tube
  • Previous ligation for sterilisation
  • Endometriosis
  • Congenital defects
  • Anovulation
  • Maternal age
  • PCOS
  • Azoospermia
  • Asthenozoospermia
  • Tertazoospermia
  • Genetic factors
  • Endometrial receptivty
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18
Q

• Describe the steps in a typical IVF cycle with reference to normal reproductive physiology.

A
  • Hypothalamic-pituitary down regulation
  • In normal menstrual cycle, e2 prodcued by the follicles negative feedback to reduce the FSH level, so the follicle with the most FSHr become sthe dominant follicle and the futhrer neg feedback causes atresia.
  • In IVF, we give exogenous FSH which means all antral follicles becomes dominant
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19
Q

• Outline the broad medical strategies for overcoming sub-fertility, including ovulation induction, IVF, ICSI and gamete donation.

A

• Induction of ovulation- aim is induce single domianant follicle , daily injection which is monitored by ultrasound
o Or you can remove the negative feedback -2 ways to do it- 1) block e2 recepptors on pituatry gonadotroph cells with selective estrogen receptor modulator (SERM) like clomid/clomiphene
o Stop e2 being made by using an aromatase inhibitor – e.g letrozole
• IVF- ovarian stimulation . hCG trigger, occyte retrieval, fertilisation in vivo, embryo culture, embryo tranfer , prego confirmation – to get the spem you do density centriguation and the live sperm end up at the bottom
• ICSI- intracytoplasmic sperm injection – used in low sperm count, low motility- single sperm injected directly into the egg

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20
Q

• Appreciate the need for fertility preservation in patients undergoing chemotherapy or radiotherapy for cancer.

A
  • Can cause premature gonadal failure

* Survival rate has increased

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21
Q

• Understand the different approaches to fertility preservation including their advantages and disadvantages.

A
  • For male- testicular tissue cryopreservation and sperm cryopreservation
  • Pre-pubescent female- ovarian tissue cryopreservation
  • Adult females- in-vitro maturation of oocyte, oophoropexy, oocyte cryopreservation, ovarian suppression
  • With occyte preservation it will take time and if the cancer is severe then they might not be able todo this. Also if the cancer cells have e2 receptors eig in breast cancer then it will be adding fuel to the flame.
  • Ovarian tissue crypopersevation -loss of follicles during the ischemic stage where vascualration had not occurred- only option for pre-puberatls and women who cant delay cancer treatment- it is available in shoety notice -limiation=efficacy is unknown and functional duration of the transplant
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22
Q

• Consider patient responses to pregnancy and cancer along with ethical issues surrounding fertility preservation

A

• Ethical implications of increasing numbers of embryos
stored in IVF clinics make oocyte vitrification a preferred
option in many cases.
• Reinsering the the disease when doing ovarian transplant- may have malignant cancer cells before freezing
• Worry about getting preg in concern that they might replapse
• Worried about birth defects as ovaries have been altered

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23
Q

• Understand the role of semen analysis in male fertility investigations

A

Normozoospermia (Normal) – All sperm parameters within normal range.
• Azoospermia – No spermatozoa found in semen sample.
• Cryptozoozpermia – Virtually no spermatozoa present – only found after extensive
search (centrifugation).
• Oligozoospermia – Sperm count/conc. <15million/ml.
• Asthenozoospermia – Sperm motility <42% (or progressive <30%).
• Teratozoospermia – Normal morphology <4%.
• Leucospermia – Leucocytes >1million/ml.
• Necrozoospermia – Proportion of dead spermatozoa outside normal range.

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24
Q

• Describe the different pathologies that adversely affect sperm production, sperm transport and ejaculation

A

• Sperm production
o Klinefelter syndrome xxy-azoospermia
o Jacobs syndrome -xyy- sperm ranging from normal to azoospermia
o xx male with sry translocation
o Y chromosme deleteion
o Cryptochroisdism- high temp comprise sperm production
o Varicocele-high testicular temp
o Testicular torsion
o Radiotherapy
o Chemotherapy
o Orchitis
o Medicines
o Anabolic steroids
• Sperm transport problems
o Absence of the vas def- can be due to mutation in cftr gene or
abnormalities in the differentiation of the mesenpheric duct
o Other obstruction in the vas def – can be caused by infection,hernia or scarring from surgery
• Erectile and ejaculatory problems
o Retrograde ejaculation- semen goes into bladder backwards , common cause is prostate gland surgery
o Other condition – erecticle dysfunction, premature ejaculation, delayed ejaculation, physical (diabetes, spinal cprd injuries- psychological- depression and stress
• Sperm antibodies
o Anti-sperm antibodies – breach in the blood -testis barrier and exposure of immunogenic sperm antigen to the immune system
o Immune response , resulting in an inflammatory reaction an d ASA formation
• Sperm DNA fragmentation
o Main cause is oxidative stress
o Free radical attack the DNA molecule causing breaks in the sperm DNA strands

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25
Q

• Understand the potential effects of sperm antibodies and DNA fragmentation on male fertility

A

• Sperm antibodies
o Anti-sperm antibodies – breach in the blood -testis barrier and exposure of immunogenic sperm antigen to the immune system
o Immune response , resulting in an inflammatory reaction an d ASA formation
• Sperm DNA fragmentation
o Main cause is oxidative stress
• Free radical attack the DNA molecule causing breaks in the sperm DNA strands

26
Q

• Define sperm capacitation and state the resulting functional changes.

A

• Influx of ca ions and HCO3 ions from the Casper and NBC channels respectively activates SACY which helps convert ATP to cAMP which then activates protein kinase a which increases tyrosine phosphorylation causing hyperactivated motiltity

27
Q

• Describe the sperm-oocyte interactions that culminate in fertilisation

A

• Once capictated they come in contact with the cumulus-oocyte complex(Coc)
• Folllicular fluid and the secretion from the COC futher modulates the spermatozoa to intitiate the process of sperm -oocyte interaction and subsequent fertilisation
• Penetration of the cumuls oophorus
o The enzyme hyaluronidase presents on the surface of the sperm head and dissolves hyaluronic acid which is a mjory cememnting factor between cells that constutuie the cumukus oophorus cell mass
• Sperm zona binding
o There’s 4 zona pellucida (ZP) glycoprotein expressed – ZP1, ZP2, ZP3, ZP4
o Studies shows that sperm binds to ZP2 and ZP3 VIA RECEPTOR PRESENT ON SPERM PLASMA MEMBRANE BUT IN HUMAN ITS ZP2
• Acrosome reaction
o triggered in response to sperm-oocyte interaction
o fusion of the sperm’s plasma membrane with its outer acrosomal membrane
o results in the release of hydrolytic and proteolytic enzymes
• Sperm-oocyte fusion and oocyte activation
o Juno-Izumo binding
o Once it binds there is an intracellular calcium spike which causes a cortical reaction
o This releases the cell from meiotic arrest and completion of meiosis 2, incorporation of sperm DNA and pronuclear formation and embryo cleavage (ovulated egg is in the metaphase 2 stages)
o Phospholipase C zeta activates the oocyte
o Breaks down PIP2 to inositol triphosphate and DAG which leads to repetitive calcium release from the oocyte’s calcium stores

28
Q

• Differentiate between normal and abnormal fertilisation using morphological criteria.

A

• Normal
o 2 pronuclei with nuclear precursor body and 2 polar body
• Abnormal
o Only 1 pronuclei but 2 polar bodies
o 3 or more pronuclei – means there is an additional set of chromosomes

29
Q

• Describe where and what is the maternal-fetal interface

A

There are 3 areas the mother and babies cell is in direct contact
• 1) syncytiotrphoblast layer covering the placenta is bathed in maternal blood
o The suncytiotrophoblast is multi nucleated layer which arises from fused cytotrophoblast . it forms a barrier and performs endocrine functions as well as has and nutreints exchange from maternal blood
• 2) invading trophoblast come into contact with decidual immune cells
o The extravillious trophoblast are differentiated fetal cells which invade into the amternal decisua to transform maternal spiral arteries
• 3)invading trophoblast come into contact with decidual blood vessels

30
Q

• Normal endometrial function

A 
•	4 layers (top-bottom)
o	Compactum 
o	Spongiosum 
o	Basalis
o	Junctional zone 
•	Initiated by withdrawal of e2 and p
•	Local mediators’ prostaglandin and PAF
•	Spiral artery vasoconstriction -ischemia and tissue damage – spiral artery relaxation – shedding of the functional endometrium
31
Q

• The management and discussion of clinical cases

A
  • Polyps -surgery

* Fribroids – medical mirena IUS or Kyleena, surgery /myomectomy, hysterectomy

32
Q

• Briefly describe implantation and maternal recognition of pregnancy

A

• Average total weight gain 9-13kg
• Baisal metabloc rate increases
• Glucose increases in maternal circulation
o First trimester – increased isluin so more glucose stored in tissue
o Second trimester – placental lactogen causes insulin resistance so more in serum
o Transfer of glucose to foetus
• Total water gain – up to 8.5 litres
• Oxygen consumption increased – Thoracic anatomy chonages- ribcage displaced upwards and ribs flare owtwards AND increased respiratory cenres senstistvity to co2 . these makes us breathe more deeply
• Increased efficiency of iron absorption from gut
• Increase in white blood cell and clotting factors , blood becomes hypercoagulable
• Red blood cell increases
• Increased appetite and thirst
• Reduced gi motility
• Relaxed lower os
• Increased filtration rate
• Increased prolactin
• Increased production of thyroid hormones
• Uterus increases in size
• Increased vascularity in cervix
• Increased mucus production

33
Q

Labour

A 
•	Quiescence phase 
o	Progesterone
o	PGI2
o	Relaxin
o	Parathyroid hormone -related peptide (PTHrP)
o	Calcitonin gene related peotide , vaso active intestina peptide 
o	Nitric oxide (NO)
o	All of these lead to increased intracellular (cAMP) or (cGMP) which inhibit the release of intracellular calcium for myometrial contractility 
•	Activation phase 
o	Rise in Oestrogen and CRH
o	Mechanical stretch 
o	Up-regualtion of panel of genes required for contraction ; prostaglandin and oxytocin receptors (OTRs)
•	Stimulation phase 
o	Prostaglandin 
o	Oxytocin 
o	CRH
o	Increased synthesis of cytokines
•	Initiation of labour 
o	Functional progesterone withdrawal 
o	Increased oestrogen bioavailability 
o	Increased responsible of the myometrium to prostaglandin and oxytocin
34
Q

• Understand the physiology of the menopause and how it is dependent on the ovarian reserve

A
  • Atleast 12 consecutive months of amenorrhea not due tp pathological causes
  • Natural event reached upon exhaustion of primordial follicles
35
Q

• Discuss the utility of AMH in assessing the ovarian reserve

A
  • Atleast 12 consecutive months of amenorrhea not due tp pathological causes
  • Natural event reached upon exhaustion of primordial follicles
36
Q

• Discuss the utility of AMH in assessing the ovarian reserve

A

• AMH is made by the granulosa cells , so if follicles are depleating then so will AMH levels

37
Q

• Comprehend the endocrine changes that underlie the menopause

A

• FSH increases as there is less eastrdiol form depleating follicles so less neg feedback

38
Q

• Be aware of the increased risk of pathologies associated with the menopause

A
  • Hot flushes and night sweats - ateiology unknown but oestrogen interacts with noradrenergic system in the brain which plays a majory role in thermogenesis. Wet flushes ocuurs as a result of inappropriate vasodilation and activation of swaet gland
  • Osteoporosis- caused by falling levels of oestrogen which impairs the normal cycle of bone remodelling by increasing amount of bone reabsorbed over the amount deposited
  • Genitourinary syndrome of meopause (GSM)- chronic, progressive ,vulvovaginal ,sexual and lower urinary tract condition charactirised by a broad spectrum of signs and symptoms.
  • Premature ovarian failure/insufficiency
39
Q

• Treatment of menopausal symptoms

A
  • Menopausal hormone therapy (MHT/HRT)
  • Plan-based, bioidentical hormones
  • CBT plus relaxation techniques – to help with low mood and anxiety
  • Regular exercise and good diet
40
Q

• Differentiation of the bi-potential gonad

A
  • After week 7 SRY switches on briefly to make the gonads into testes and I absence ovaries are formed
  • Testis develop 2 important hormones known as Sertoli cells (AMH) and Leydig cells (testosterone)
  • SRY is a DNA binding protein that cats as a transcription factor , the binding site is upstream of SOX9 which is also a transcription factor
  • Sox9 can bind its own upstream activation site, so its levels remain high even if SRY declines (positive feedback mechanism)
  • Sox9 acts to stimulate the expression of further downstream genes
  • Sox9 does thiy by stimulating the production of prostaglandin D2 by the pre Sertoli cells. This acts as a paracrine hormone to stimulate further sox9 prodcution in these cells. This e-enfroces al precursor cells along the Sertoli pathway
  • Sox9 also stimulate production of fibroblast growth factor 9 (FGF9) which acts as chemotactic factor for cell migration into the developing testis and production of SOX9
  • Sox9 also stimulate production of AMH and inhibiton of female transcription factors WNT4 and FOXL2
  • The precursor of bipotential gonads are formed from the common somatic meschymal tissue prescursos called genital ridge primordia
  • Primordial germ cells -become sperm or oocyte
  • Primitive sex cords – become Sertoli or granulosa cells
  • Mesenephric cells – become blood vessels and Leydig or theca
41
Q

• Mullerian and Wolffian ducts and control of their differentiation

A
  • Mullerian ducts – inhibited in the male by AMH

* Wolffian ducts – stimulated by testosterone and lack of stimulation by testosterone means regression in female

42
Q

• Differentiation of the external genitalia

A
  • Testosterone coverted to a more potwtn version DHT in the genital skin by 5 -a-redurtasse
  • DHT binds to the testosterone receptor and causes differentiation of clitoral area into penis, labia fusion aand becomes ruggated to form the scrotum and a prostate forms
43
Q

• Introduction to psychosexual development

A

• Gender role expression or portrayal of psychological characteristics
that are considered sexually dimorphic within the general
population (eg. toy preferences / physical aggression etc).
Gender identity self-representation or identification as male or female
(or neither).
Sexual orientation refers to choice of sexual partner and erotic interest
(eg. include heterosexual, bisexual, homosexual).
• Amygdala larger in males? A brain region involved in
emotional processing. Its size is positively correlated with
aggressive behaviour across species.
Left amygdala more active in women? Associated with
emotional memories. Right amygdala is associated with
action.
Hippocampus contains more grey matter in females?
Involved in memory & social cognition.

44
Q

• Causes and consequences of defects in sexual differentiation

A

• Gonadal dysgenesis - Sexual differentiation is incomplete. Usually
missing SRY in male, or partial or complete deletion of second X in
female. Also used as a general description of abnormal development of
the gonads.
Sex reversal - Phenotype does not match genotype, ie may be male
genotypically but externally look like a female.
Intersex - Have some components of both tracts or have ambiguous
genitalia. Sex of infant difficult to determine.

45
Q

• Androgen Insensitivity Syndrome

A

• In xy individual
• Testosterone made but has no effect
• AMH made so Mullerian ducts regress
• No differaton of wollfian ducts and no external male geniatlia
• Complete AIS
o Undescended testes, no uterus or fallopian tubes and external genitalia appear female. Usually present with primary amenorrhoea and alck of body hair is clue
• Partial AIS

46
Q

• Persistent Mullerian Duct Syndrome

A
  • XY male , unable to resposn to AMH in utero
  • Type 1 results from mutation of the gene for AMH on chromosome 19
  • Type 2 results from mutations of the gene for AMH receptor on chromosome 12
  • Tetses form and either failt to male AMH or AMH recptr absent
  • Mullerian duct remain
  • Differentiation of Wolffian ducts and masculinised external genitalia
  • Treatment – surgery to retrieve testes and psoititon then in the scrotum
47
Q

• 5-Alpha-Reductase Deficiency

A
  • Xy , testosterone made not to dht
  • Testes form – AMH made- Mullerian ducts regress -wollfian develols but no external male genitalia
  • May appear mainly female or ambiguous genitalia
48
Q

• Turner Syndrome

A
  • 45 xo
  • Streak ovaries -shows we need to x for ovarian development
  • Uterus and tubes present
  • Wide spectrum of phenotopic disorders and severity
  • May be fertile
49
Q

• Congenital Adrenal Hyperplasia

A
  • Xx female exposed to high levels of androgen in utero
  • Failure to synthesis cortisol
  • Hypothalamus secrete CRH and cats on pituatry to produce ACTH which acts on adrenal glands and it produce cortisol which feedbacks negatively to hypotahalams and pituatruy
  • Possibility of salt wasting due to lack of aldosterone
  • Mascualnised external geniatlia
50
Q

• Understand the importance of chromosomes, genes, DNA

A
  • Gives unique progeny through fusion of haploid cells from mother and father
  • This prevents the accumaulation of genetic mutations
  • Increases in genetic diversity
51
Q

• Contextualize the processes of mitosis and meiosis with relevance to formation of gametes.

A

• Games ?- haploid cells speacialised for sexual fusion with 23 chromosomes in total
• gametes go through cycles of diploidy & haploidy
• Gametes are formed from germ line cells: primordial germ cells that migrate into the gonad and then differentiate to either male or female gametes
• –The process producing oocytes – oogenesis (incorporated as part of folliculogenesis)
• –The process producing sperm - spermatogenesis
• –Undergo cycles of mitosis to increase numbers
• –Then undergo meiosis
• –Then combine at fertilisation
• Chromosomes replicate during S-phase of cell cycle
• Interphase , mitosis (prophase, metaphase,anaphase,telophase
• Mitosis
Interphase- not condensed then duplicates to become 2chromatid, cell replicates its centrosomes which contains apair of centrioles
Prophase -chromatin coils and condenses resulting in compacted chroksomes which can be visible under a light microscope
Prometaphase -the nuclear envelope breaks down and microtubule coming from the centrosome attach to a structure on the chromosome known as the kineticore found on the centromere
Metaphase – the centrosomes alligh at the centre in a straight line at the equatorial plate
Anaphase -the centromere pairs from each chromosomes sepreates and move towards the poles
Telophase – the sepaerating chromosome reach the poles and cytokinesis occurs and nuclear envelope forms
• Meiosis
Interphase- not condensed then duplicates to become 2chromatid, cell replicates its centrosomes which contains apair of centrioles
Prophase 1 -chromatin coils and condenses resulting in compacted chroksomes which can be visible under a light microscope, the centrosomes form the mitotic spindle . this diploid cell has pair of homologous chromosmes which pair up and the pairing is called synapsis , nuclear envelopme breaks down . the chromosmes also exchange genetic material through whats known chrossing over at chiasmata
Methaphase 1: the centrosomes alligh at the centre in a straight line at the equatorial plate
Anaphase 1 - the centromere pairs from each chromosomes sepreates and move towards the poles
Telophase 1- the sepaerating chromosome reach the poles and cytokinesis occurs and nuclear envelope forms
Prophase 2- the chromatin again condenses to chromosomes
Metaphase 2- the chromosomes line up on the equatorial plate
Anapahase 2- the sister chromatids separates
Telophase 2 – chromosomes again decondense and nuclear membrane reforms

52
Q

• Compare and contrast these processes in male and female gametes

A

• X chromosome → 1000 working genes
• • Y chromosome → 86 working genes
• Male :
Start with spermatognium which becomes primary spermatocyte(46) (mitosis)
Splits 2 secondary spermatocyte (23 each) (miosis 1)
Each splits into 2 more giving 4 spermatozoa (23)(meisosi 2)
• Female
Start with oogonium undergo mitosis and one become the primary oocyte (23) and another become first polar body (23) the polar body then divides into 2 more polar bodies and the primary oocyte becomes

53
Q

• Understand the concept of genetic variability and the consequence of aneuploidies

A

• Independent Assortment
–homologous pairs of chromosomes line up at the equator (midpoint) of the spindle during metaphase I.
–However, the orientation of the members of the pair is random with respect to which member is closer to which pole.
• Crossing Over (Recombination)
– Corresponding pieces of chromatids of
maternal and paternal homologues (non-sister chromatids) are exchanged during synapsis
when the homologues are aligned side by side.
– Each of the affected chromatids has a mixture of maternal and paternal genetic information
• A gain or loss of chromosomes from the normal 46 is called
• aneuploidy, affecting normal development and functioning.
• • Since each chromosome contains hundreds of genes, the addition or
• loss of a single chromosome disrupts the existing equilibrium of the
• cell leading to profound phenotypes.
• • Using cytogenetics (including karyotyping) - aneuploid gametes
• produced at surprisingly high rates in humans
• Non-disjunction – failure of homologous chromosome to
• separate during MI or sister chromatids to separate during
• MII, resulting in extra or missing chromosomes
• 50% of recognized pregnancy loss result from chromosomal abnormality.
• • Most common aneuploidies in humans are trisomies (0.3% of live births).
• • Viable ones are:
• – Trisomy 21 (aka Down’s syndrome, 1:750 births)
• – Trisomy 18 (Edwards syndrome)
• – Trisomy 13 (Patau syndrome)
• • 50% of patients with primary amenorrhea as a
• result of premature ovarian insufficiency (POI)
• have an abnormal karyotype
• • Sex chromosome aneuploidy more viable,
• usually random event (not inherited):
• – Turner syndrome (45, X monosomy) » caused by complete or partial absence of
• 2nd sex chromosome (occurrence 1:2000 female births) → phenotype=short
• stature, primary amenorrhea (classic Turners)
• – Klinefelter syndrome (47,XXY trisomy) » caused by presence of two X and one Y
• chromosome (occurrence 1:500 male births) → variable phenotype=taller than
• average, small testes producing reduced testosterone, infertility

54
Q

• Why does crossing over occur in x and y chromosome apart from at the pseudoautsomal regions (PAR)

A

• They are hemizygous to each other & so
recombination proved harmful
– PAR allows the X & Y chromosomes to pair and
properly segregate during meiosis in males

55
Q

• Describe the regulation of the HPG axis by hypothalamic hormones – Kisspeptin and GnRH.

A

• GnRH neurons are expressed in 2 regions
-Arcuate nucleus
-Medial preoptic nucleus
• These neurons synthesis and secrete GnRH
• GnRH makes its way through the median eminence to the abterior pituarty gland- does it thru the hypophyseal portal system
• Kisspeptin receptor -GPR54
• Kisspeptin role as gate keeper of puberty , also controls synthesis and seceretion of GnRH in GnRH neurons
• Acts upstream of GnRH
• Kp54 able to ross the blood brain barrier bery effecintly so is used in-vivo animal study
• In-vitro study- ks-10 used as its an active ligand and is also cheaper to make
• Kiss1R expressed on GnRH neuron
• GnRH
Synthesised and secreted from GnRH neurons , secreted in apulsatile manner
• GnRH is secreted in pulses from
• hypothalamus every 30-120min
• Slow frequency pulse favours FSHb
• transcription and FSH release, rapid pulse frequency favours LHb transcription and LH release

56
Q

• Discuss the roles of gonadotrophins and gonadal steroids.

A 
•	Gonadotrophin hormones :
Glycoproteine
Heterodimeric
Pulsatile
Common alpha subunit , different beta subunit
•	Follicle-stimulating hormone (via FSHR)
• Testis:
- regulation of Sertoli cell metabolism
• Ovary: 
- follicular maturation
- granulosa cell estrogen synthesis
Luteinising hormone (via LHR)
• Testis: 
- stimulation of Leydig cell androgen synthesis
• Ovary:
- theca cell androgen synthesis
- ovulation
- progesterone production of corpus luteum
•	Male gonadal steroid production
-Leydig cells 
LHR expression 
Androstenedione, 
DHEA, Testosterone 
production
-Sertoli cells
FSHR expression 
Sertoli cell metabolism
Testosterone 
dihydrotestosterone
•	Female gonadal steroid production
1.	Theca cells
LHR expression
Testosterone and 
Androstenedione
2.	Granulosa cells 
FSHR expression 
Oestradiol and 
Oestrone
•	Steroid Hormones
Progesterone
• Oestrogens
• Oestradiol and also oestrone
• Androgens
• Androstenedione, testosterone, dihydrotestosterone
57
Q

• State the role of inhibin in HPG axis feedback.

A 
•	Inhibin 
Peptide hormones
• Heterodimers
• 2 isoforms of inhibin: A and B.
• Inhibin = gonadal, inhibits FSH secretion via 
direct negative feedback to anterior pituitary.
• Males: Inhibin B 
• Females: cyclical dependent
58
Q

• Define puberty and differentiate between its two endocrine events.

A 
•	Puberty - Continuum of changes leading to somatic and sexual maturation
• Profound physiological, psychological and physical changes
• Reproductive perspective: goal to produce mature gametes
Breast development in females, and increased testicular volume in males
•	2 endocrine events of puberty 
Adrenarche:
- Adrenal 
androgens
- Growth of pubic 
hair, axillary hair
Growth in height
Gonadarche 
-LH/FSH
- LH - steroid synthesis --> 
secondary sex characteristics
FSH - growth of testis 
(male)/steroid 
synthesis/folliculogenesis 
(female)
Several years after adrenarche
59
Q

• Describe the endocrine processes and events underpinning adrenarche and puberty.

A

First endocrine process of puberty
Occurs ~6-8 years
• Characterised by (re-)instigation of adrenal androgen secretion
• Dehydro-epiandrosterone (DHEA)
• Dehydro-epiandrosterone sulphate (DHEA-S)

60
Q

• What instigates adrenarche?

A

ACTH?
• Dexamethasone suppresses adrenal androgen production
• Children with ACTH receptor mutations fail to undergo adrenarche.
• But, no change in ACTH/cortisol during adrenarche
• ?Divergent mechanisms for cortisol and androgen production at
adrenarche?
2. POMC?
• Proximal 18 AA region that positively regulated adrenal androgen production.
• In vitro studies did not substantiate this
3. POMC-related peptides?
• b-lipotrophin and b-endorphin plasma levels correlate with increased DHEA/S at adrenarche

61
Q

• Understand the molecular events governing the onset of adrenarche and puberty.

A

16th gestational week activation of HPG axis.
– Pulsatile GnRH secretion in foetus and 1-2 years postnatal increased.
• Neurones ‘restrained’ during postnatal period  10 years or more
• At puberty a gradual rise in pulsatile release- around 1 year before
breast budding observed
Potential adverse risks from early puberty:
- cardiovascular disease
- metabolic disease
- obesity
- diabetes
- disordered behaviour
- decreased adult height
- decreased life expectancy
Extremes of energy excess (body fat mass) impact the timing of puberty
in both sexes - particularly females
• Under- and over-nutrition in foetal and/or neonates alters the timing of
puberty in rodents and humans
• Morbid obesity (females) can cause precocious puberty

Year 3 (2 decks)

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