Hormones can be: modified amino acids (adrenaline), peptides (somatostatin), proteins (insulin), cholesterol derivatives (steroids).
Most hormones are stored in intracellular membrane-bound secretory granules, and are released by calcium-dependent mechanisms. Lipid-soluble hormones cannot be stored (unless they are thyroid hormones which are stored in the glycoprotein matrix) they come from SER and mitochondria rich cells.
Most protein and peptide hormones activate cell surface receptors coupled to G-proteins or have intrinsic tyrosine kinase activity. Receptors for lipid soluble hormones are usually within the cell and directly modify gene transcription.
Hormones are inactivated by metabolic transformation in the liver or at the site of action, usually the smaller the hormone, the faster it is inactivated.
Hormones: homeostasis, reproduction, growth and development, metabolism
Steroid proteins work with HSP (heat shock proteins) these are receptors which have hsp attached to their active site, preventing them from binding to DNA sequences. The function of steroid proteins is to bind to hsp and make them detach from the receptor, allowing it to bind to and cause changes in the transcription of DNA genes.
Only non-bound hormones are biologically active, so when considering the effect of a hormone, you don’t just want to know how much of it is produced, but also how bound it is.
Located on the anterior of the trachea just below the larynx.
Releases two hormones: thyroxine T4 and triiodothyronine T3 = their main effect is thermogenesis, inducing an increase in the metabolic rate. Also crucial in growth and development.
Thyroglobulin is a glycoprotein, the main constituent of colloid, to which T4 and T3 are attached to not escape. PENDRIN moves colloid back into the cell for release preparation.
An iodine and sodium symporter transports Iodide into the cell using the sodium gradient.
The amino acid tyrosine is iodinated to form either mono MIT or diiodotyrosine DIT, which are then coupled to form either thyroxine (DIT+DIT) or triiodothyronine (DIT+MIT).
Thyroid stimulating hormone TSH is released from the anterior pituitary, TSH is regulated by TRH from the hypothalamus in response to the thermoceptor, T3 and T4 levels.
T3 levels are around 1/6 of T4 levels, and most of them both are usually bound to TBP (thyroxine binding protein) anyways, so are usually unavailable to their receptors, which are inside their target cells. T3 is about 10 times as potent as T4 so it is rarely given to patients. T4 is more tightly bound to proteins. T3 has a much shorter half life than T4
Thyroid receptors are present in almost all tissues and are especially high in the liver and low in spleen and testes.
Primary role of the hormones is an increase in synthesis if Na+ K+ ATPase - you need ATP for this - so metabolic rate rises - oxygen consumption rises - erythropoiesis rises.
There is no expected value for T3 and T4 in people, great variation
SS: weight loss, warm skin/heat intolerance, diarrhoea, exophthalmos, lid lag, palpitations, anxiety, tremor, goitre (bruit), brisk reflexes (whole body in overdrive)
Ca: Grave’s disease, Toxic multi nodular goitre and toxic solitary nodule goitre, De Quervain’s thyroidits, cancer (very rare), amidarone induced
I: TFTs (thyroid function tests) low TSH, high T3 and T4, ultrasound scan of nodules, fine needle aspiration of solitary nodules to rule out malignancy, isotope scan to assess hot and cold thyroid
I: thyroid uptake scan: check how iodine goes in the gland: if it is overactive, it goes in very fast. If too much goes in, it is probably Grave’s disease
T: Conservative: patient education, smoking cessation. Medical: symptomatic control (palpitations and tremor: beta-blockers, eyes: drops for lubrication), antithyroid medication (carbimazole: the one most commonly used, but takes long to act, propylthiouracil: it prevents peripheral conversion of T4 to T3 too so it is very fast acting, rarely used. agranulocytosis (lowered white blood cell count) is a common side effect, needs monitoring, more susceptible to infection), Radioactive iodine ablation (definitive treatment, patients must be euthyroid before treatment) Surgical: subtotal thyroidectomy (patients must be euthyroid (their levels of thyroid hormones checked?) before surgery. Potassium iodide before surgery decreases thyroid gland vascularity so it is done)
Co: Atrial fibrillation, high output heart failure, cardiomyopathy, osteoporosis
Grave’s disease: most common cause, autoimmune, ocular changes distinguish it from others, associated with other autoimmune conditions (pernicious anaemia)
Toxic multi nodular goitre and toxic solitary nodule goitre: second most common cause, increased risk with age, more common in females, single nodule is suggestive of thyroid neoplasia.
De Quervain’s thyroiditis: transient hyperthyroidism after viral infection, goitre is often painful, period of hypothyroidism may follow
HCG induced hyperthyroidism: HCG and TSH share the same structure, so too much HCG can cause overproduction of Thyroid hormones, this is what you see in early pregnancy
Amiodarone induced - some medication containing iodine increases thyroid hormone production
Extra: because there is a lot of storage of thyroid hormones, it does take a long time in general before the effect of medication for hyperthyroidism to kick in
Young women: are usually resistant to anti-thyroid medication (surgery first), large goitre probably won’t respond well/sufficiently to medication (surgery), cosmetic reasons (surgery)
TEMPORARY TREATMENT for hyperthyroidism: you give treatment for 12-18 months, you slowly reduce it, then you stop. If treatment hasn’t started working in 3-6 months then you need to consider surgical options, because it won’t work.
SS: weight gain, cold skin/cold intolerance, constipation, dry skin, thinning of hair, bradycardia, depression, delayed reflexes (everything slows down)
Ca: Primary (issue within the thyroid gland itself) iodine deficiency, Hashimoto’s autoimmune thyroiditis, post-thyroidectomy/radioactive iodine, drug-induced (lithium, hyperthyroidism overtreatment) Secondary (issue with the hypothalamic-pituitary axis): pituitary adenoma, Sheehan’s syndrome (ischaemic necrosis of the pituitary gland after childbirth), infiltrative disease (tuberculosis, haemochromatosis)
I: TFTs (High TSH, low T3 and T4), thyroid antibodies, FBC (anaemia) U&Es (urea and electrolytes, checking kidney function), LFTs (liver function tests), creatinine, cholesterol, Guthrie test for congenital screening
T: Conservative: patient education (diet change), medical (LIFELONG replacement of thyroid hormone with levothyroxine)
Co: Hypercholesterolaemia, pre-eclampsia, hyperthyroidism from over treatment of hypothyroidism, myxoedema coma (coma caused by sever hypothyroidism)
Hashimoto’s thyroiditis: production of antibodies against thyroglobulin or thyroid peroxidase
GOITRE: low levels of thyroid hormones will stimulate the HPA and get stimulation of the thyroid, overgrowth
Can cause fluid retention: oedema and heart failure.
Has an effect on GAGs which is why hair and skin are affected
LIFELONG TREATMENT as oppose to temporary for hyperthyroidism
Cancer that originates from follicular or parafollicular cells. Caused by malignant neoplasm, increased risk with childhood neck irradiation.
SS: thyroid nodules/solitary nodule, rarely: hypothyroidism/hyperthyroidism
I: good family history (also for them, it is autosomal dominant), lumps (which can vary in size and increase very fast-weeks or months, and usually painless), TFTs, calcitonin (tumour marker), ultrasound (you can tell if it is benign or malignant: hypoechoic=bad, microcalcifications=bad, increased vascularity=bad
Types: papillary (70%, young, spreads to cervical lymph nodes, good prognosis), follicular (20%, low iodine areas, spreads to bone and lungs, good prognosis), medullary (from parafolicular cells, calcitonin marker, MEN syndrome, spreads to lymph), anaplastic (older patients, aggressive, spreads, poor prognosis)
Treatment: usually thyroidectomy and lifelong levothyroxine and annual thyroglobulin measurements. (anaplastic usually just palliative care)
Has three layers: Glomerulosa (aldosterone), Fasiculata (glucocorticoids), Reticularis (sex hormones).
If there is over function of adrenal gland: Cushing’s, if there is under function: Addison’s.
Pituitary gland produced ACTH - stimulates the Adrenal cortex to produce Cortisol
Cortisol: mAkes glucose in the liver, Antistress pathways, Anti-inflammatory pathways
Collection of signs and symptoms occurring when a patient has long-term exposure to cortisol (has exogenous or endogenous causes), difficult to diagnose.
SS: Buffalo hump, acne, moon face, central obesity, hypertension, hyperglycaemia, striae (different to stretch marks because they are depressed on their surface, fresh so dark, there is bruising), vertebral collapse, proximal muscle wasting (this does not happen with metabolic syndrome, so it is a good way to rule this out if other symptoms look like metabolic syndrome), psychosis, thinning of skin (also not in metabolic syndrome)
I: Diagnostic: urinary free cortisol, low dose and high does dexamethasone (not given to people on antiepilepsy medication because they would metabolise it anyways) suppression test Bloods: FBC, U&Es, LFTs, glucose, lipid levels Radiology: CXR (looking for lung cancer and vertebral collapse) Other: Dual energy X-ray Scan Note- it is a very difficult condition to diagnose because no one test can fully confirm or disprove Cushing’s
T: Conservative: education about the condition, decrease alcohol consumption (alcohol increases cortisol levels) Medical: ketoconazole, metyrapone, mitotane, treat complications: hypertension and diabetes mellitus Surgical: trans-sphenoidal surgery to remove pituitary adenoma or bilateral adrenalectomy to remove adrenal adenoma if indicated
Exogenous causes: iatrogenic (eg prescription of glucocorticoids for asthma)
Endogenous: either adrenocorticotrophic hormone dependent (ACTH) or ACTH independent ACTH dependent: Cushing’s disease (from pituitary) too much is produced from an adenoma, low dose dexamethasone test is used to confirm. Ectopic ATCH production in Ectopic Cushing’s (usually from a small cell lung cancer). ACTH independent: CARS: Cancer (adrenal adenoma), Adrenal nodular hyperplasia, Rare causes (McCune - Albright syndrome), Steroid use.
Cushing’s disease = pituitary problem Cushing’s syndrome = adrenal problem Ectopic Cushing’s = being produced elsewhere (eg small cell carcinoma of lung)
Arenal insufficiency, wherein the adrenal glands do not produce enough steroid hormone. A type of primary adrenal failure. Usually under diagnosed.
SS: unintentional weight loss, skin pigmentation (hand folds), body hair loss, constipation, abdominal pain,
Causes: MAIL: Metastasis from breast, lung, renal cancers; Autoimmune, Infections (tuberculosis most common, and opportunistic in HIV), Lymphomas (Inflammation, infiltration, infection, ischemia)
Random cortisol is enough to confirm suspicions for Addison’s to the extent that you can start treatment, this is a medical emergency, you do not wait for a full set of tests.
If you have adrenal insufficiency, you need to replace all hormones that are produced by the glands, hydrocortisone and glucocortisone - you cannot have an Addison’s patent who is not on glucocortisone
Hyperkalaemia can be a slight effect of Addison’s.
T: Conservative: education, carry a steroid alert card. Medical: replace glucocorticoids and mineralocorticoids with hydrocortisone and fludrocortisone, treat complications Surgery: surgical excision of tumour, if indicated.
Germ layers: ectoderm (epidermis, nervous system), mesoderm (muscles, bones, connective tissue), endoderm (other organs, GIT, respiratory tract)
Important dates in embryology: DAY 6 (implantation-enters uterine cavity), DAY 9 (blastocyst-16 cells embedded in endometrium, lacunae formation), DAY 15 (gastrulation)
Day 8: division of embryoblast (forms embryo: hypoblast, epiblast) and trophoblast (forms chorionic sac: syncytiotrophoblast - implantation enzymes and cytotrophoblast)
Peak vulnerability is weeks 3-8 (embryonic period) when the majority of organs are developing, after that the foetal period will have less of an impact.
Causes of embryonic defects: 54% unknown
14% genetic factors (mutations in genes, chromosomal aberrations, trisomy Down’s-accumulations of lymph just below the neck, palmar crease, disposition of ears, deletions DiGeroge, translocations sex-reversal syndromes with SRY_mutations with loss or gain in function in coding regions Apert’s syndrome, achondroplasia-dwarfism or in promoter/enhancer sequences, Lieberberg syndrome, sex-reversal syndromes)
7% environmental factors (drugs, chemicals, infections, diabetes, obesity)
35% multifactorial inheritance (interaction of multiple genes with environmental factors, eg folate intake)
Alcohol causes decreased expression of shh, DNA mutations, metabolic changes due to trying to remove the alcohol, cellular death
Anencephaly (open brain), spina bifida (failure of spinal closure)
If you have spina bifida, 10% die in their first year, so in utero surgery is required before 26 weeks (otherwise the open contents of the spine will be exposed to the urine and toxins in the amniotic fluid, and the neural tube will degenerate) By day 24 the brain and neural tube are closed
Spina bifida occulta is a malformation of one or more vertebra: can be a birthmark, dimple, but the spinal chord can also be tethered to the vertebra and can be damaged as the child grows
Folic acid (VitB) can reduce the occurrence of spina bifida by up to 70% (otherwise combination of low folate with a folate metabolism genetic mutation can cause pathologically low levels of folate in the embryo)
Valproic acid causes the slowing of neural tube
MESODERMAL DEFECTS skeletal, limb patterning, spondolocostal dysostosis - defects with the generation of somites, achondroplasia - FGR3 mutation causing hyperactivity and decreased chondrocytes thus smaller bones, digit formation - morphogens different levels are needed to determine the digit type so you can get 5432112345 if you have the same amounts coming from both sides then diffusing, arm to leg transformation - Leibenberg syndrome because of misexpression of PitX1 in the wing making it a leg
ENDODERMAL DEFECTS lung aplasia, oesophageal atresia, emphalocele,
NEURAL CREST ABNORMALITIES contribute to the peripheral nervous system and melanocytes and face - so cleft lip and palate defects, underdevelopment of lower jaw - Pierre Robin sequence, Hirschprung’s disease - failure of the formation of the enteric nervous system, so endless expansion of the GIT
FEMALE REPRODUCTIVE SYSTEM
Hypothalamus GnRH - pituitary LH, FSH - ovaries/testes testosterone, estradiol, progesterone
By the time of onset of puberty, you have 0.5million oogonia, and then the numbers keep dropping until menopause = the amount of time it takes to get rid of those 0.5million primary follicles.
FOLLICULAR PHASE 1-10: FSH (anterior pituitary gland) - growth and maturation of the primordial follicle, induces LH receptors (competing to become the dominant follicle), suppressed by inhibin (from ovarian granulosa cells)
Oestrogen (ovaries and placenta) - produced by the ovary during follicular maturation, stimulates glandular proliferation of the inner lining of the endometrium, stimulates the synthesis of progesterone receptors (makes endometrium secretory in preparation for the fertilised ovum) - negative feedback on FSH and LH, but rising levels of oestrogen towards the end of the follicular phase sensitise the pituitary gonadotrophs to GnRH, resulting the massive preovulatory LH surge and triggering of ovulation
The mature follicle produces less oestrogen and more progesterone, together with GnRH they cause a massive release of LH in the bloodstream
OVULATION 11-14: LH (anterior pituitary gland) - induces ovulation
LUTEAL PHASE 15-28: The follicle (without the ovum now) becomes a progesterone-secreting corpus luteum
If there is no fertillisation, the corpus luteum produces less and less progesterone as it runs its lifespan and becomes the corpus albicans - the spiral arteries shrivel, the endometrium collapses and the lining is lost.
Progesterone (corpus luteum, placenta, adrenal cortex, testes) is responsible for cramping because it usually relaxes the uterus and prevents it from contracting, but when progesterone drops, the uterus begins contracting again and this causes pain.
First part of the cycle oestrogen has a positive feedback on LH, in the second part of the cycle it has a negative feedback on LH
Purpose of transvaginal scans is to examine: ovaries, endrometrial lining, uterus size and orientation
Female infertility can be caused by: egg issues, egg transportation issues, cavity/implantation issues
EGG ISSUES: follicular stage (no eggs or no egg maturation), luteal phase (issue with tubal transport, implantation)
Hypothalamic origin: hypogonadotrophic hypogonadism (hypo-hypo) low BMI under 20, high intensity exercise - reversible within a few months; radiation, tumour, injury, infection - you cannot reverse. Issue: no GnRH. Solution: give them GnRH (this is an easy solution, but if it doesn’t resolve, the issue may be at a different level) Complications of gonadotrophin therapy - OHSS overstimulation, many follicles, multiple pregnancies, ascites (extreme), renal failure, elements of these found in 3-4% of patients so should be checked for.
Pituitary origin: prolactin secreting tumour most common, psychiatric medication, hyperprolactinemia (high levels of prolactin inhibit the release of GnRH), TRH increases, increases prolactin production - check iron, if you fix the thyroid you fix the issue, or give them dopamine to suppress production.
Hypotrophic Hypogonadism: there is not enough GnRH being produced so the follicles are not being stimulated - type I
Hypertrophic Hypogonadism: there is enough GnRH, and therefore FSH but there are not enough follicles to be stimulated, so there is no LH surge or ovulation - Type III
Hyperprolatinemia: high levels of prolactin negative feedback on GnRH so low levels of FSH
No eggs at all: ovarian failure (nothing you can do) or dysfunction (you can try and stimulate them) clomiphene citrate (first line, stimulates FSH release) letrozole (when clomiphene doesn’t work) stops oestrogen production.
PCO vs PCOS. Polycystic ovaries = you scan ovaries and there are cysts. PCOS Type II = there may or may not be cysts because you only need 2/3: cysts, irregular periods, increased male hormones in blood or associated symptoms
TUBAL ISSUE: inflammatory disease - ascending infection, fallopian tube abscess, fluid that seeps back into the cavity, destroying the embryo even if the person got pregnant as it is embyrotoxic. Catheter and dye and Xray to check the tubes for size and leakage.
UTERINE ISSUES: Hysteroscopy (examination of the inside of womb), you can see polyps to be removed, submucosal or subserosal fibroids, endometriosis or uterine abnormalities.
MENOPAUSE AND OVARIAN INSUFFICIENCY
At birth: 1-2mill, puberty 300k, by menopause therefore, on average 400 oocytes ovulated
All arrested in phase 1 of meiosis 1 - this is why there is a huge atresia rate, they are stuck in this phase for tens of years, meiosis ii only completed when the egg is fertilised.
1 female oocyte - 1 egg (1 to 4 in men)
LMP over a year ago is how you define menopause (retrospectal diagnosis), you don’t test if over 45 bc expected, only test in women without a uterus, or women who are less than 45yo
FSH is high (because no feedback from ovaries to produced oestrogen), oestrogen is therefore low.
At 54, 80% of women are thought to be postmenopausal.
Climateric/perimenopausal = the period of time around menopause
Symptoms: anovulatory cycles, menorrhagia (abnormally heavy menstrual bleeding), physical and psychological issues due to hypooestrogenism (oestrogen receptors are everywhere: breasts, skin, urogenital tract, bone, brain, blood vessels) hot flashes (2 years)
Osteoporosis because oestrogen/estradiol induces growth factor activation, has antiresorptive activity
NONHORMONAL TREATMENT: lifestyle measures (less caffeine, alcohol, no smoking), vaginal lubricants, oestrogen (unless they have breast cancer), low does SSIs for mood swings, Clonidine for hot flashes
Progesterone (does not help with bones, but counteracts the negative effects of oestrogen: unopposed oestrogen will cause endometrial growth - hyperplasia, cancer, given to women with endometriosis and without a uterus too, because may cause pain and recurring symptoms)
Testosterone (not in the NHS but privately and lower doses, male testosterone given to improve energy levels and libido, only to be taken if already taking oestrogen, otherwise no effect)
Given continuously every day - no breakthrough bleeding, or sequential preparations (continuous oestrogen, but progesterone withdrawal in 1/4 weeks for breakthrough bleed - given in the first two years, may have erratic ovarian function)
BENEFITS: protect bones (especially in women undergoing early menopause), reduces colorectal cancer incidence, alleviates symptoms - has to be started in perimenapause, not possible after around 10 years
RISKS: breast cancer (overall risk still smaller than 14units of alcohol a week), endometrial cancer if taken wrong, CV risk if taken at the wrong time (too late)
TYPES: oral (young women prefer this) transdermal (lowest risk because bypasses system, oestrogel, testosterone is gel, local oestrogen in vagina or gentle areas, can be used in women with breast cancer too
POI premature ovarian insufficiency - a lot of delayed diagnosis from primary care, 1% of women under 40, 0.1% of women under 30, 0.01% of women under 20. 80% idiopathic (no known cause, rule out Turner or mosaic turner), streak ovaries; FMR1 permutation (fragile X syndrome), anti-adrenal and anti-thyroid antibodies (autoimmune); strong family history
Younger women can be given COCP instead of HRT
INVESTIGATIONS AND TREATMENT OF INFERTILITY
Infertility is defined as the inability to achieve a pregnancy after one year of regular, unprotected sexual intercourse. After 1 year - 84% couples, 2 years 49% (92% overall), 3 years 15% - the longer you’ve tried, the less the changes of achieving natural conception.
Age of the female is the most significant factor affecting the changes of pregnancy.
Primary sub fertility: trying but can’t get pregnant for the first time, secondary sub fertility: has had one child but cannot get pregnant a second time
I: How long have they been trying? How regularly are they trying? What pregnancies have they had together or in previous relationships? Other lifestyle factors.
FEMALE I: cycle regularity (most important thing to find, even than tests and measurements), weight/change in weight, drugs, risk of tubal disease (STI, ectopic pregnancies, surgeries, infections, even ruptured appendix), history of endometriosis (risk factor for tubal disease)
MALE I: occupation (not usual to have radiation and temperature, but you can ask), testicular maldescent (many men haven’t had surgery until 8-9 yo, which may have had irreversible detrimental effect on sperm production), trauma, infections (STIs, mumps orchitis-infection where if acquired by adults could cause damage in testes itself, affects testicular sperm production), surgery, erectile dysfunction
BASIC INVESTIGATIONS: ovulation (regularity), egg quality (female age); semen fluid analysis (concentration, motility, morphology), if just one of the three isn’t ideal, it shouldn’t greatly affect fertility; pelvic anatomy and tubal patency; previous surgeries; fibroids; HSG; laparoscopy (only when you suspect an issue you can fix or when you have inconclusive results otherwise); endometriosis
Check FSH levels, if there is low follicular reserve, there will be no negative feedback on the FSH, so it’s levels will be abnormally high - this is a diagnostic tool (there may be variability month to month, so if you get a normal result, retest, while a high FSH level is always significant)
AFC count with pelvic ultrasound and measure - there soul die 7-8-9 every month
AMH (anti-mullerian hormone test) - first line test used now, the more eggs you have the more granulosa cells you have - the more AMH you have. Valuble because little inter-cycle variability, can be measured at any time within the cycle and can be measured on women on contraception too.
HepB, HepC, HIV are tested in everyone coming in with fertility issues. Also Rubella check and booster immunisation vaccine given if needed
Hyrdosalpinx is fallopian type filled in fluid
IVF bypasses the fallopian tubes if they were the issue, it also can inject sperm into the egg if there is an issue with the sperm.
CONTROL OF TESTICULAR FUNCTION AND PHYSIOLOGY
Testes need to be 2 degrees below body temp (which is why there is an issue with their descent it needs to be resolved very soon, otherwise it will cause permanent damage and possible infertility)
Seminiferous tubule cells produce sperm, Leydig cells produce testosterone, Sertoli cells are supportive cells between them, they maintain the integrity of spermatogenesis, support, protection, control, secrete what is needed - they are connected to one another separating the basal cells from???? in order to isolate the newly formed sperm cells from the immune system, as they are producing new antigens this is the blood-testicular barrier done by the sertoli cells
120 million sperm produced per day, up to 10 weeks needed for one cell to mature
Acrosome is the tip of the sperm cell, containing lysosomal enzymes to penetrate the egg; lots of mitochondria for movement of the tail
Hypothalamus GnRH - anterior pituitary FSH, LH - seminiferous tubules (spermatogenesis) LH on the interstitial cells of Leydig: testosterone (which generates negative feedback on LH)
NO POSITIVE FEEDBACK (all negative, unlike in women where there is positive feedback: oestrogen increases LH - ovulation)
If you have very low levels of LH and FSH you are not producing enough sperm or testosterone, so the first measurement you make is checking LH and FSH levels
4h after ejaculation sperm become hyper energised, there is cholesterol loss and calcium influx
Cortical granules stop polyspermatic penetration
High levels of testosterone suppress sperm production
Spermatogenesis inhibition: immune (blood-testicular barrier damage, body forms anti-sperm antibodies, immobilises sperm and incapacitates them) - this is why vasectomy works well but cannot be easily reversed after 5 years: increased intra-testicular pressure due to vasectomies breaks the blood-testicular barrier, so even if anatomical reversal is possible, physiological reversal may be impossible: levels of sperm antibodies need to be checked before consideration
A lot of oestrogen in food (from the urine of women taking the contraceptive pill, animals being fed oestrogen, pollution of food chain from excessive sources of oestrogen) has caused a decline in the number of sperm in western countries
Kleinfelter Syndrome is 47XXY
Kallman Syndrome - lack of formation of anterior pituitary properly and lack of development of sense of smell (so if someone looks 15 when 40 and cannot smell) give them LH and FSH and they should become fertile
Androgen insensitivity syndrome 46XY: female phenotype but abdominal testicles which may become cancerous because of temperature (the testicles should only be removed after puberty to allow them to grow to their maximum height.