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Transitions - puberty and menopause Diana Stamatopoulos and Shreya SrinivasContent ⮚ What is puberty? ⮚ HPG axis activation ⮚ Physiological events of puberty ⮚ Tanner stages ⮚ Male disorders ⮚ Female disorders ⮚ Menstruation ⮚ MenopauseWhat is Puberty? • The period in which adolescents reach sexual maturity and are capable of reproduction, and is a well defined sequence of physical and physiological events resulting in full sexual and physical maturity. • Reactivation of the HPG axis. • Global variation in timing and speed – influenced by genetic, environmental and metabolic factors. • Female Onset -> 8-13 years old • Male Onset -> 9-14 years oldHPG axis• 3 periods of HPG pulsatility. • Intra-uterine HPG – weeks 10-24 gestation. • Postnatal – 1-6 months. • Classic Puberty – 8-14 years. • ‘Mini-Puberty’ -> transient postnatal HPG activation and sex steroid surge. Reproductive organ development; body composition and growth; cognitive function; and behaviour.Initiation of classical puberty 1. Kisspeptin (polypeptide) and other neuropeptides like neurokinin B released by neurons in the arcuate nuclei of the hypothalamus → GnRH secretion from the pituitary. 2. GnRH acts on the anterior pituitary to release gonadotrophins LH and FSH. 3. LH and FSH act at the gonads to release testosterone (males) and oestrogen and progesterone (females). 4. Raised GH,gonadal steroids, and IGF-1 → characteristic pubertal growth spurt Leydig + Sertoli cells in testes → convert cholesterol to testosterone. Theca + Granulosa cells in ovaries → produce oestrogen and progesterone.Physiological events • Adrenarche -> pre-pubertal awakening of the adrenal glands. 2 years prior to gonadarche (6-8 years) and is the production of adrenal androgens (DHEA, androstedione). • Gonadarche -> between 8-14 years, and is the onset of true central puberty, and is the increase in production of sex steroids. (F = oestrogen and progesterone, M = testosterone). Re-activation of the HPG axis, and production of pulsatile GnRH, and increasing FSH + LH. • Pubarche -> development of pubic hair. • Thelarche -> female breast development (normally the first sign in girls). • Spermarche -> first ejaculation, coincides with development of 2 nd characteristics in males. • Menarche -> menstruation, around 2 years after thelarche. • ‘Growth Spurt’ -> peak growth velocity in childhood after infancy – Tanner stage 2-3 for girls (prior to menarche), and 3-4 for boys.Tanner stagingDisorders of puberty Early - precocious puberty Late - delayed puberty Contra-sexual development - physical features of the opposite sex.Precocious puberty Defined as onset of puberty before the age of 8 in females, and before age 9 in males. Causes: ▶ Idiopathic - Influenced by: parents puberty, weight, normal variant ▶ Gonadotrophin dependent or central - Early activation of the HPG axis - Dysfunction of the hypothalamus or pituitary - Tumour releasing GnRH or HCG - Infection or radiation - affects negative feedback mechanism ▶ Gonadotrophin independent or peripheral - Abnormal overproduction of sex hormones - Tumours of the gonads - Genetic: McCune Albright syndrome - Hyperthyroidism - Adrenal gland: Congenital adrenal hyperplasia, tumours - Exogenous steroids (medications) Delayed puberty Defined as lack of pubertal signs at an age that is 2-2.5 standard deviations later than the population mean, typically by the age of 13 years in girls and 14 years in boys. Causes: ▶ Functional - Excessive physical exercise - Malnutrition and eating disorders - systemic illness ▶ Lack of gonadotrophins - hypogonadotrophic hypogonadism - Congenital or acquired - Idiopathic - Kallmann syndrome (+ anosmia) - Pituitary tumour, prolactinoma - Trauma ▶ Gonadal insufficiency - hypergonadotrophic hypogonadism - Radiation - Klinefelter syndrome (XXY) and Turner syndrome (45X) - Ovarian insufficiency - Orchitis/anorchia/cryptorchidism ▶ Obstructive Key investigations and treatments Precocious puberty ▶ Tanner scale and orchidometer ▶ Gonadotrophin levels - LH and FSH (high) ▶ Raised testosterone/oestrogen/progesterone ▶ Imaging: Ultrasound or MRI looking for structural causes like tumours in the brain or in the gonads Delayed puberty ▶ Tanner scale and orchidometer ▶ non-dominant wrist x-ray ▶ Gonadotrophin levels - LH and FSH (low in hypo-hypo, high in hyper-hypo) ▶ GnRH stimulation test ▶ Prolactin ▶ TFT ▶ Imaging - USS or MRI ▶ Karyotype Treatment options: ▶ LH, FSH, HCG injections - fertility ▶ Testosterone or oestrogen - puberty ▶ Dopamine agonists ▶ Surgery for some tumours ▶ GnRH analoguesMCQ 1 An 18-year-old male is referred to the endocrinology clinic with a history of short stature compared to his peers and parents, poor libido, lack of pubic hair growth and lack of penis growth during his teenage years. Blood tests show; total testosterone as 5.4 nmol/L (low); FSH 1.7 IU/L (low); LH 1.8 IU/L (Low). He has no other past medical history and has no children. On examination his testes have a volume of 5ml and are soft on palpation, and a penis length of around 6cm. He notes a history of a poor sense of smell from as long as he can remember. What is the most likely diagnosis? A – Chemotherapy induced testicular damage B – Orchitis C – Klinefelter's D – Kallman’s E – Normal delayed pubertyMCQ 1 An 18-year-old male is referred to the endocrinology clinic with a history of short stature compared to his peers and parents, poor libido, lack of pubic hair growth and lack of penis growth during his teenage years. Blood tests show; total testosterone as 5.4 nmol/L (low); FSH 1.7 IU/L (low); LH 1.8 IU/L (Low). He has no other past medical history and has no children. On examination his testes have a volume of 5ml and are soft on palpation, and a penis length of around 6cm. He notes a history of a poor sense of smell from as long as he can remember. What is the most likely diagnosis? A – Chemotherapy induced testicular damage -> Hyper Hypog. B – Orchitis -> Hyper Hypog. C – Klinefelter’s -> Hyper Hypog. D – Kallman’s -> Hypog Hypog, small testes, few 2 ndcharacteristics, loss of smell. E – Normal delayed pubertyMCQ 2 A 15-year-old girl presents to the GP as she has not yet started her periods. On examination, she is 145 cm tall and has a BMI of 19kg/m². She reports her mother and older sister both started menarche at 14 so believes the delay may be normal for her family. A. Congenital adrenal hyperplasia B. Constitutional delay C. Turner syndrome D. Premature ovarian insufficiencyMCQ 2 A 15-year-old girl presents to the GP as she has not yet started her periods. On examination, she is 145 cm tall and has a BMI of 19kg/m². She reports her mother and older sister both started menarche at 14 so believes the delay may be normal for her family. A. Congenital adrenal hyperplasia B. Constitutional delay C. Turner syndrome → short stature, low AMH suggesting low or no ovarian follicles D. Premature ovarian insufficiencyDisorders of Female PubertyDisorders to Cover ● Hypogonadotropic hypogonadism ● Premature ovarian insufficiency ● Hyperprolactinaemia ● Congenital adrenal hyperplasia ● Androgen tumour ● Doping ● Gonadotropin secreting tumour ● Chemotherapy ● Asherman syndrome ● Polycystic ovarian syndrome (PCOS) Hypogonadotropic hypogonadism Low FSH, LH + E2 •Maturation of the HPG axis must occur for menstruation, which is dependent on body fat •History – weight loss, over-exercise, stress or illness. •May be organic in origin due to pituitary failure or cancer, but more likely due to low BMI. May be due to hyperprolactinemia. •Management – lifestyle, oestrogen replacement via sequential HRT or COCP (may cause headaches, tender breasts, nausea). Pregnancy needs GnRH/FSH/LH injections. •Dopamine agonists/surgery for high prolactin. Premature Ovarian Insufficiency •High FSH/LH + low E2. •<40 – can be iatrogenic, autoimmune, genetic. •History – family history, menopausal symptoms (night sweats, poor concentration), Turner’s (XO – run out of eggs as a neonate). •Examination – atrophic vaginitis, small ovaries, no follicles. •Risks: Osteoporosis and CVD. •Management: HRT, COCP or egg donation. IVF is used for pregnancy. Hyperprolactinemia •High PRL – PRL inhibits FSH/LH. Dopamine inhibits PRL – use bromocriptine (agonist). •History – galactorrhoea, bitemporal hemianopia, headaches. •Causes – tumour or drugs such as antipsychotics + antiemetics which are dopamine antagonists. Hypothyroidism as TRH stimulates PRL. •Causes anovulation – FSH/LH injections with concomitant use of antipsychotics. Congenital Adrenal Hyperplasia •High testosterone •Late menarche and infrequent periods, with hirsutism. •Adrenal issue with a block to 21-hydroxylase that makes cortisol, and precursors increase and convert to androgens. Decreased cortisol also causes an ACTH rise – hyperplasia. •Incomplete block as a complete loss would cause a neonatal crisis. •Synthetic ACTH will not cause an increase in cortisol – suppress ACTH with low dose replacement of cortisol to reduce androgens. Androgen Tumour •Ovarian or adrenal – rapid onset, hirsutism and virlisation (breast atrophy, baldness, enlarged clitoris). •Very high testosterone. •MRI, CT + US to diagnose. Doping •Anabolic steroid use causes increased muscle mass, reduced FSH/LH and increased androgens. Gonadotropin Secreting Tumour •Progressive headaches and visual field defects. •High FSH/LH + E2. •Multiple ovarian cysts and follicles. •Most are non-functional. Chemotherapy •May cause direct damage to ovaries. •Requires egg donation and oestrogen to prevent osteoporosis early on in life. Asherman's Syndrome •High LH + E2. •History – prior termination or miscarriage. •Cyclical discomfort but normal pelvic examination. •Normal cycle, but a thin and abnormal endometrium on transvaginal ultrasound. No endometrial growth and scarring due to the walls sticking together. •Curettage to break down adhesions, and a copper coil to hold the walls apart for regrowth – removed after 4 months. Polycystic Ovarian Syndrome High LH + Testosterone. •History – hirsutism, acne, T2DM and weight gain. •Infrequent periods and arrested follicle development. •Examination – BMI, insulin resistance, acne and ultrasound of ovaries. High lH causes increased androgens and paused growth of follicles, but not of those regulated by AMH. •Diagnosis -> requires 2 of: menstrual irregularity, clinical or biochemical androgen excess or multiple cysts determined by transvaginal US. •Management – COCP to suppress gonadotropins, weight loss + metformin for insulin resistance. •Oestrogen antagonist (clomiphene citrate) at start of cycle to balance FSH + LH ratio and promote egg growth. Unable to lower LH without lowering FSH – must increase FSH.Pathogenesis of PCOSMCQ 1 A 17-year-old girl presents to the GP with concerns about not having started menstruating. On examination, she has a BMI of 16. She also has a body fat percentage of 17%. The girl also tells the GP she is an avid runner and hockey player but has recently been stressed a lot due to her upcoming exams. What is the most likely biochemical result? A – high PRL, low FSH + LH + E2, normal testosterone. B – normal PRL, high FSH + LH, low E2, normal testosterone. C - normal PRL, normal FSH, high LH + normal E2, high testosterone. D - normal PRL, low FSH + LH + E2, normal testosterone. E – normal PRL, low FSH + LH, high E2, normal testosteroneMCQ 1 A 17-year-old girl presents to the GP with concerns about not having started menstruating. On examination, she has a BMI of 16. She also has a body fat percentage of 17%. The girl also tells the GP she is an avid runner and hockey player but has recently been stressed a lot due to her upcoming exams. What is the most likely biochemical result? A – high PRL, low FSH + LH + E2, normal testosterone. -> hyperprolactinaemia. B – normal PRL, high FSH + LH, low E2, normal testosterone. -> premature ovarian insufficiency. C - normal PRL, normal FSH, high LH + normal E2, high testosterone. -> PCOS. D - normal PRL, low FSH + LH + E2, normal testosterone -> She mostly likely has hypogonadotropic hypogonadism due to low body weight/over-exercise preventing re-activation of HPG axis. E – normal PRL, low FSH + LH, high E2, normal testosterone. -> normal.MCQ 2 A 32-year-old woman presents to her GP with recurring night sweats that soak through her sheets, as well as poor concentration at work and joint stiffness. She notes a history of early menopause in her family. On ultrasound, she has small ovaries with no follicles. Biochemical results show an FSH >30 (high), and low oestrogen levels. What is the most likely diagnosis? A – Premature Ovarian Insufficiency B – Early menopause C – Ovarian Cancer D – PCOS E – Aschermann’s SyndromeMCQ 2 A 32-year-old woman presents to her GP with recurring night sweats that soak through her sheets, as well as poor concentration at work and joint stiffness. The woman also tells the GP she has had very infrequent periods. She notes a history of early menopause in her grandmother and aunt. On ultrasound, she has small ovaries with no follicles. Biochemical results show an FSH >30 (high), and low oestrogen levels. What is the most likely diagnosis? A – Premature Ovarian Insufficiency -> menopausal symptoms with infrequent periods <40 is highly indicative of POI, especially with a high FSH and low oestrogen level. B – Early menopause -> <40 menopausal symptoms is not normal variation and is indicative of something more clinical. C – Ovarian Cancer D – PCOS -> PCOS would cause a cystic appearance of the ovaries, and would show normal FSH, high LH and normal oestrogen, with increased androgens. E – Aschermann’s SyndromeMenstruationMenstruationØFollicular/proliferative – FSH + LH stimulate oestradiol production by the primary follicle and allows endometrial growth. Oestrogen prevents other follicle growth and thins cervical mucus. ØFeedback switches to positive feedback of oestrogen to cause LH to increase. ØLH surge – day 14 = Ovulation ØSecretory – Corpus luteum secretes progesterone creating a receptive uterus. ØNo implantation = Regression of CL = Menstruation ØImplantation – Embryo produces hCG to replace LH to maintain CLMenopause What is Menopause? Permanent cessation of menstruation due to loss of ovarian follicular activity (quantity and quality). Decline is gradual. Clinical definition - >12 months of no period. ØNormal 45-55; early 40-45; POF <40 (based on serum FSH - >30) ØFactors affecting age – genetics, ethnicity, smoking, alcohol, hysterectomy, oophorectomy, radiotherapy.Menopausal Symptoms ØUterus – loss of muscle. ØCervix – decreased secretions. ØOvaries – decreased follicles. ØOviducts – shrinkage and loss of ciliated epithelium and mucosa. ØVagina – loss of elasticity, shortening, decreased secretions, thinning epithelium, dryness, increased tears, bleeding and infection. ØVulva, bladder and urethra undergo atrophy – UTI’s, burning and discomfort. ØFunction of lower genital tract is dependent on oestrogen. ØVasomotor symptoms (night sweats, hot flashes) ØReduced libido, dyspareunia, mood lability and irritabilityComplications and Risks - CVD + Osteoporosis ØCVD – oestrogen promotes vascular remodeling and elasticity, regulates reactive dilation and local inflammation. Leads to impaired endothelial function and vascular changes. ØOsteoporosis – uncoupling of bone remodeling, increased resorption and decreased bone mass. ØOestrogen acts directly on osteoblasts to limit RANK-L, so demolition = construction. when oestrogen declines, this inhibition is lost and more RANK-L is produced, so there is more osteoclast recruitment. ØRANK-L is regulated by mechanical environment and PTH. RANK-L activates osteoclasts to start resorption. OPG is a RANK-L decoy receptor which binds to osteoclasts and prevents resorption. ØFracture threshold for insufficiency fractures is met earlier in women as bone mass gradually declines from age 40 in both sexes, both loss of oestrogen causes rapid decrease. Management of Menopausal Symptoms ØAppropriate risk factor screening before prescribing* ØHysterectomy – with unopposed oestrogen (note: endometriosis - add progesterone*) ØUterus and recent menstruation: oestrogen with 14 days of progesterone and then a withdrawal bleed or continuous oestrogen with a Mirena implant (IUD) ØNo menstruation and uterus – oestrogen and progestogen/Mirena (IUD) ØLubricants, oxybutynin, SSRI/SNRI + gabapentin for hot flushes and sweats ØVaginal oestrogen; testosterone (libido)Risks and Benefits of HRT ØBenefits – symptom control, bone and heart protection, decreases LDL cholesterol Ø<40 for bone and CV protection even with no symptoms. <60 at risk of fracture and non-oestrogen treatment is unsuitable. ØIncreaed stroke risk with oral. Transdermal oestrogen can be used for appropriate symptoms (vaginal atrophy) ØRisk of VTE ØIncreased risk of breast cancer, endometrial cancer (oestrogen-only) ØOestrogen can cause breast tenderness, cramps, headaches and bloating / Progesterone can cause backache, depression and tenderness. ØOral HRT Contraindications – BMI >30, gallstones, liver disease, enzyme inducing drugs, VTE risk, malabsorption, diabetes. MCQ 1 A 56-year-old woman presented to her GP two weeks ago with a history of night sweats, hot flushes, vaginal dryness and atrophy, and painful sex. She also said she was feeling more anxious and struggling with concentrating at work and at home. The GP told her she was menopausal, and to come back and discuss possible treatment regimens. The woman had a hysterectomy at 42-years-old, has a medical history of hypertension, diabetes and a BMI of 37. She also has a faily history of breast cancer. What is not an appropriate treatment? A – Transdermal oestrogen for her vaginal atrophy B – Weight loss C – Oral HRT D – Lubricants E – Self-help MCQ 1 A 56-year-old woman presented to her GP two weeks ago with a history of night sweats, hot flushes, vaginal dryness and atrophy, and painful sex. She also said she was feeling more anxious and struggling with concentrating at work and at home. The GP told her she was menopausal, and to come back and discuss possible treatment regimens. The woman had a hysterectomy at 42-years-old, has a medical history of hypertension, diabetes and a BMI of 37. She also has a family history of breast cancer. What is not an appropriate treatment? A – Transdermal oestrogen for her vaginal atrophy -> transdermal oestrogen is suitable for people with high risk of CVD and stroke. B – Weight loss C – Oral HRT -> high risk of CVD, stroke and breast cancer. Oral HRT is not appropriate, even though she is <60. D – Lubricants E – Self-helpMCQ 2 A 46-year-old woman presents to her GP with menopausal symptoms, such as hot flushes and dizziness, as well as increasing joint stiffness. She had a hysterectomy 5 months ago, to help manage her endometriosis. She has a BMI of 23 and has no other prior medical history. The woman is keen to start any treatment that will help mediate her symptoms. Which regimen is the most appropriate? A – Unopposed oestrogen B – COCP C – Continuous oestrogen and Mirena D – Continuous oestrogen and progestogen E – Progesterone onlyMCQ 2 A 46-year-old woman presents to her GP with menopausal symptoms, such as hot flushes and dizziness, as well as increasing joint stiffness. She had a hysterectomy 5 months ago, to help manage her endometriosis. She has a BMI of 23 and has no other prior medical history. The woman is keen to start any treatment that will help mediate her symptoms. Which regimen is the most appropriate? A – Unopposed oestrogen -> endometriosis. B – COCP C – Continuous oestrogen and Mirena -> no uterus to place an IUD. D – Continuous oestrogen and progestogen -> Unopposed oestrogen is not generally appropriate with endometriosis in case of risk of endometrial deposits, so progestogen is given to protect against any deposits risk of cancer. E – Progesterone onlyResources that might be useful: https://www.aafp.org/pubs/afp/issues/1999/0701/p209.html - useful summary tables for timeline of puberty and disordersFeedback Please take a minute now before you leave to fill in a quick feedback form: https://app.medall.org/feedback/feedback- flow?keyword=820e15b1e83645e926b1282a&organisation=accessibility-in-medicine AIM Facebook Page ▶Give our Facebook page a like for updates and opportunities,just search @AIMEdinburgh Thank you for coming! ▶ If you have any more questions, feel free to email me at s2463905@ed.ac.uk, or email accessibilityinmedicine@gmail.comSign up to the mailing list ▶ Sign up to the AIM mailing list to be the first to hear about tutorials, discounts, and opportunities! ▶https://forms.gle/q JNyeoFzA9B5urND7Thank you to our sponsors: