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Transitions: Puberty and Menopause Yr 2 26/11/2024 Tutor: Lewis Gilmartin, Lucy RobinsonLearning Outcomes Puberty ▶ Physiological events and stages of puberty ▶ Puberty onset ▶ The growing skeleton - skeletal growth and relevant hormones ▶ Disorders of puberty Menopause ▶ The ageing skeleton - peak bone mass ▶ Menopausal changes ▶ Onset of menopause ▶ Management of menopausal symptomsPubertyPuberty - Physiological Events ▶ First stage is a intrauterine activation of the “HPG axis”. ▶ This is followed by “mini-puberty” as a 1-3 month old lasting till 6 months old. The exact purpose of this remains unclear but rapidly influences the reproductive organ development of newborns and stimulates the fastest rate of growth during human life. Its thought this may “program” the timing of ▶ Its termed mini-puberty due to activation of the HPG axis that goes onto trigger puberty later in life. ▶ undergo puberty. Genetics plays a big role. Its thoughty minipuberty may “program” the timing of later puberty. HPG axis Hypothalamus - Pituitary - Gonads You may have encountered this before in your endocrine control of fertility. This is a neuronal and endocrine tissues that function together that trigger the onset and regulation of puberty. Briefly GnRH neurons release GnRH that act on the anterior pituitary glands to release Gonadotrophs LH and FSH. They have variant effects depending on the sex but important to know. Female: LH acts on theca cells that produce androgen precursors. FSH acts on granulosa cells that use the precursors to make androgens Male: LH acts on Leydig cells to produce testosterone.Puberty - How does it know when to start? ▶ This axis will become quiescent after 6 months and will remain in the juvenile/childhood stage for many years. ▶ Although the HGP axis is a self sustaining loop once activated there needs to be some system to “ignite” the axis in the first place ▶ There are two theories as to what triggers this Kisspeptin release the “genetic clock” which begins the wind down the inhibition of Kisspeptin and the HGP axis. ▶ The somatosensory states that there are various signals such as body mass and energy ( particularly fat) that signal the body is ready. ▶ It’s generally accepted both are at play, we will come back to how this can go wrong. KNDy neurons -> Kisspeptin -> GnRH neurons -> Pulsitile GnRH Puberty “ Marks the end of childhood” Period in which adolescents will reach sexual maturity and are capable of reproduction. Female - Starts at ages 8 - 13 ( avg. 10.5) Male - Starts at ages 9 - 14 ( avg. 11.5) There is a sexual dimorphism between male and females, with females on average starting puberty around 1 year earlier. Age variation within these limits is normal and everyone should go on till achieve a well defined sequence of physical and physiological events, and has no impact on future sexual and physical maturity ( i.e fertility and appearance).Quantifying and stages of puberty. There are many stages all of which end “arche” ( ARK-ee) Adrenarche - awakening of the adrenal gland zona reticulata ( this makes DHEA which is the precursor of androgens ( testosterone and estrogen)), a pre-pubertal stage that normally occurs around 2 years before the gonadarche. Gonadarche - 8-14, onset of true puberty. This phase increases pulsatile release of GnRH from the hypothalamus which increases release of gonadotrophins of LH and FSH. Initial growth of testis and testosterone ( M). Growth of breasts and estrogen production. Pubarche - Development of pubic hair, often alongside Gonadarche Thelarche - Development of breast tissue (F) slight gynecomastia in (M). Spermarche - Onset of sperm production, often mid way through puberty (M) Menarche - Onset of the menstrual cycle (F)Tanner staging Aka: Sexual maturity rating (SMR) - Female Stage one ( pre-pubertal): Adrenache + elevation of papilla Maintains childhood growth rate. Stage two ( pubertal): Breast bud (Thelarche) + sparse growth of labia fine and straight hairs (Pubarche) . Rate of height growth accelerated. Stage three: Darker, denser and curled pubic hair. Breast enlargement and areola. This is the fastest rate of growth (post infantile) Menstruation is quite variable its typically around 12.5yrs within stage 3 or 4. Body fat composition influences this with higher body % having a quicker onset on menstruation.Tanner stage - F cont. Menstruation is quite variable its typically around 12.5yrs within stage 3 or 4. Body fat composition influences this with lower body fat % delaying first menstruation by >1 year ( non pathological weight) Stage four: Adult pubic hair around groin ( but not thigh). Regular periods ( variable). Growth rate slowing. Projection/pointing of the areola Stage five: Adult genitalia, cessation of height growth ( around 16). Pubic hair spread to medial thigh and breast contour typically larger than lateral thorax.Tanner stage - F referenceTanner staging Aka: Sexual maturity rating (SMR) - Male Stage one ( pre-pubertal): <3ml testicular volume, maintaining childhood growth rate, no pubic hair or penile growth. Adrenarche Stage two ( pubertal): There is a increase in testicular size change ( but not penile change). Pubic hair present, decreased body fat%. Thinning and reddening/pigmentation of scrotum. No change in growth rate. Stage three: Increase in testicular size ( 6-12ml), voice breaks/deepening tone, height growth rate increasing. Slight gynecomastia and increased muscle mass.Tanner staging - M cont. Stage four: Fastest rate of growth ( post infant), axillary hair, acne and body oder. Mostly adult pubic hair but not medial thigh. Continued penile and testicular growth (12 - 20ml). Stage five: Growth rate will slowly drop off. Rapid increase in muscle mass. Full adult male body hair and penile growth. Testicular volume ( 20 - 35ml).Tanner stages - M referencePuberty - The Growing Skeleton Ossification is the process of creation and formation of new bone structure, in the human skeleton this will take place via only 2 key processes Endochondral ossification: Named after the fact that happens inside (endo) a cartilage ( chondral) scaffold. This is the process that occurs at the physis of bones and hence is what responsible for linear growth. Intramembranous ossification: It happens when osteoblasts lay down osteoid within a fibrous membrane ( and not cartilage). This process in embryonic flat bones ( such as the skull) and subperiosteal bone growth ( the process of making bones wider and fatter). The focus will primarily be on endochondral and long bone growth.The growth plate/epiphyseal plate We are born with more bones that disconnected and fuse together as we age. They fuse via growth within the growth plate which start life as weak loose chondrocytes. These chondrocytes proliferate ( replicate) producing a harder cartilage, but not bone. These chondrocytes will eventually undergo hypertrophy ( swell) and apoptosis release their stored calcium.Bone growth cont. The death of the chondrocytes leaves behind a calcified ECM called the primary spongiosa. Osteoprogenitor cells can turn this messy “woven bone” into a secondary spongiosa or “laminar bone”, which is much stronger.Explosion of pubertal hormones influence bones and body structure. • Hormones determine skeletal and body composition. • Testosterone -> increased bone density and growth acceleration – shoulder width and facial bones grow disproportionately. • Increased shoulder : hip ratio. • Increased muscle bulk – post-skeletal (doubles by adulthood). Peak strength velocity occurs 1-2 years after height. • Oestrogen -> fat distribution to bum, hips, thighs + more subcutaneous fat in the face. Lower average muscle mass – increased body fat %. • Increased bone density and growth of widened pelvis, and increased hip anteversion. Opposite shoulder : hip ratio and a different gait (sway).Direct effects on bones correlate with the differences in the sexes. Just to highlight the key differences in Testosterone and Oestrogen, keep in mind that males and females produce both, but in differing amounts. Testosterone acts directly on the chondrocytes to enhance their proliferation and hypertrophic effects. Explaining the average increased height in males. Oestrogen acts to promote that stage of fusion/ossification of the growth plate. This explains why females have such a quick drop off in their maximum height during the 5th tanner stage, but males have a longer drop off often into their late teens and early 20s.Puberty - Disorders of Puberty Very simply is it too early or is it too late? Precocious puberty is secondary sex characteristics <8 in F, <9 in M. Delayed puberty is no secondary or incomplete secondary sex characteristics >13 in F, >14 in M. AT THIS STAGE ALL YOUR ARE LOOKING FOR IS A SIGNIFICANT DEVIATION IN TANNER STAGESHistory! Any indication that something may be wrong you will get from the history of a question. - Nutritional deficiencies, significantly underweight ( i.e hypogonadotropic hypogonadism) which will delay puberty - Cancers particularly anywhere within the HPG axis OR adrenal gland. This typically brings on puberty too early. - Conversely treatment of any cancer via radio/chemotherapy is a massive risk for delayed puberty. - Thyroid issues - Hyper = Too early. Hypo = Too late. - Significant time spent in NICU/PICU, serious L.D or brain injury and rarer causes but this is more Peads returning in 5th year.MenopauseMenopause ▶ Permanent cessation of menstruation that marks the end of reproductive competence when there is a loss of ovarian follicular activity (decrease in both quality and quantity of oocytes residing in ovarian follicles) ▶ There is a loss of ovarian hormonal function (due to oocyte loss) which result in the menopausal symptoms ▶ Officially menopause when periods have stopped for 12 months ▶ Perimenopause is when menopausal symptoms are present but the periods have not stopped completely or the 12 month mark has not been reachedMenopause ▶ Average age of onset is 51 years or between 45-55 years ▶ Abnormal early menopause is defined as menopause occurring in someone <40 years old (due to primary ovarian insufficiency, premature ovarian failure, etc.) ▶ Factors affecting menopausal age ▶ Genetics and ethnicity ▶ Smoking/substance abuse ▶ Reproductive history ▶ Chemotherapy, pelvic radiotherapy ▶ Oophorectomy or hysterectomyMenopauseMenopause - The Ageing Skeleton ▶ Peak Bone Mass - the point when the skeleton has the greatest amount of bone tissue in a patient's life ▶ Occurs at the very end of skeletal maturity (mid to late twenties) ▶ The value depends on factors like gender, dietary intake of calcium and their general health. ▶ At menopause, there is a significant drop of oestrogen levels in females leading to a rapid decline in bone mass.Menopause - Oestrogen and Bones ▶ Osteoclasts - resorb bone ▶ Activated by RANK-L ▶ Osteoblasts - forms bone ▶ Oestrogen inhibits bone resorption by inhibiting expression of RANK-L ▶ Has a protective effect on bones ▶ Note: osteoclast bone resorption is increased by PTH via RANK-L and decreased by calcitonin directly and oestrogen via RANK-L inhibition ▶ Note: osteoblast formation is increased by PTH, vitamin D, oestrogen and growth hormoneMenopause - Oestrogen and Bones ▶ Oestrogen levels drop at menopause and thus the protective effect they had on bone is lost, leading to increased osteoclast activity and lower bone density (more at risk of osteoporosis)Menopause - Osteoporosis ▶ Osteoporosis - reduced bone quantity but at a microscopic level the bone is the same (i.e. same quality of bone) ▶ Fracture risk in women >60yo is twice that of men >60yoMenopause - Oestrogen Effects ▶ Inhibits FSH ▶ Vaginal lubrication ▶ Endometrial changes ▶ Breast growth ▶ Bone growth ▶ Immune system regulation ▶ Cardiovascular system regulation ▶ Thermoregulation ▶ Mood regulationMenopause - Menopausal Changes Bodily Changes ▶ Changes in lower genital tract - oestrogen regulates the function of the female genitals. Menopausal oestrogen decline results in tissue atrophy of the vagina, vulva, bladder and urethra. ▶ Vaginal dryness, dyspareunia (painful intercourse) ▶ Vulvar pruritus - dry itchy skin particularly around vulva ▶ Burning and discomfort ▶ Recurrent UTI ▶ Uterus loses muscularity due to lack of use through the cessation of menstrual cycles ▶ Fallopian tubes shrink and lose cilia and mucous, contributing to the loss of fertilityMenopause - Menopausal Changes ▶ Vasomotor symptoms - will reduce once menopause is over ▶ The loss of follicles and therefore oestrogen, progesterone, AMH and inhibin B as well as the desynchronised secretion of GnRH, LH and FSH contribute to symptoms commonly associated with menopause ▶ Hot flushes, night sweats, cold sweats, heart palpitations and blood pressure changes ▶ Mood and sleep changes ▶ CV disease increase, hypertension - loss of oestrogen leads to activation of RAAS ▶ Osteoporosis - loss of oestrogen protective effect Note: a postmenopausal women can still technically get pregnant and give birth if they are provided with an egg and exogenous hormones required to prepare the uterus for implantation and maintain pregnancyMenopause - Onset ▶ The HPO axis (hypothalamus-pituitary-ovarian) maintains the reproductive competence and gonadal hormone secretion (oestrogen and progesterone) ▶ Their is a progressive and ultimately accelerating loss of ovarian follicles as women age and so even in premenopause, the oestrogen levels are slowly decreasing due to reduced follicle numberMenopause - Onset ▶ In perimenopause, their is an accelerated loss resulting in variability in follicle development and ovarian secretion, ultimately leading to the final menstrual cycle ▶ Oestrogen levels decrease faster than in premenopause until they eventually level out once menopause is reached due to cessation of menstrual cycles Note: there is still some oestrogen in the body postmenopause despite there being no follicles left to produce it as the ovaries produce androstenedione/testosterone which get converted into oestrone - a weaker oestrogen than oestradiolMenopause - Ovarian Follicle Loss ▶ There is continuous oocyte apoptosis and oocyte depletion in each menstrual cycle a women goes through ▶ Duration of ovarian functionality is mainly determined by the extent and rapidity of this oocyte apoptosisMenopause - Ovarian Follicle Loss ▶ Female reproductive aging is gradual so as women age, their follicle numbers get smaller but as do their follicle quality. ▶ Smaller, less functional follicles produce lower levels of oestradiol which normally inhibits FSH release. ▶ Instead, FSH levels rise as women age, messing up the timings of when oestradiol levels increase during the cycle and therefore impairing LH surge timing. ▶ Thus, ovulation is accelerated and the follicular stage is shortened hence perimenopausal women tend to have shorter intervals between menstrual cycles.Menopause - Hormones ▶ The decreasing levels of oestradiol and inhibin B (due to lower number and poorer quality of follicles), the negative feedback loop seen in the HPG axis is lost resulting in increased levels of GnRH, FSH and LH (15 fold increase in FSH and a 10 fold increase in LH) ▶ FSH levels can be used to confirm perimenopause (FSH>30) ▶ If over 45 years, vasomotor symptoms and irregular periods are enough to diagnose perimenopauseMenopause - Hormones Note: inhibin B is produced from follicles hence why levels are low in menopauseMenopause - Hormones Throughout Life ▶ Early reproductive stage - variable to regular menstrual cycles ▶ Peak reproductive stage - regular menstrual cycles ▶ Late reproductive stage - regular menstrual cycles but low FSH, AMH and follicle count then eventually subtle changes in period flow and length with variable FSH, low AMH, low inhibin B and low follicle count ▶ Early menopause - variable menstrual cycle length with variable and elevated FSH, low AMH, low inhibin B and low follicle count ▶ Late menopause - interval of amenorrhoea (no menstrual cycles) and elevated FSH, low AMH, low inhibin B and low follicle count ▶ Early postmenopause - variable and elevated FSH, low AMH, low inhibin B and very low follicle count ▶ Late post-menopause - FSH stabilises, very low AMH, very low inhibin B and very low follicle count Note: AMH is Anti-Müllerian hormone; the higher the AMH, the more follicles there isMenopause - HRT ▶ Almost always helps with vasomotor symptoms but symptoms will return after stopping HRT ▶ Hot flushes, night sweats, cold sweats, heart palpitations and blood pressure changes ▶ Benefits - symptom control, improved quality of life, bone and cardiovascular protection ▶ Risks - side effects (sometimes solved by reducing oestrogen or progesterone dose), medical contraindications, breast cancer (same risk as obesity or drinking alcohol), ovarian cancer, thrombosis (with oral HRT) ▶ Contraindications: after breast cancer, E2 receptor positive gynae cancer and oral HRT is contraindicated if risk of thrombosisMenopause - HRT ▶ HRT contains oestrogen and progesterone: ▶ Oestrogen for symptoms - given has pill, patch, spray, gel as the same dose every day ▶ Progesterone to protect the endometrium from oestrogen - patch, tablet, Mirena implant Note: oestrogen is not given on its own as it could cause endometrial hyperplasia or endometrial cancer unless the patient has had a hysterectomy and does not have endometriosis (even after a hysterectomy, endometriosis deposits are very sensitive to stimulation by oestrogen in patients with endometriosis) ▶ Give progesterone for 14 days on then 14 days of to patients who have only finished menstruation recently which results in bleeding in the off period. ▶ We don't give them constant progesterone as they still have some of their own ovarian function so are still making their own hormones and it would result in uncontrolled, chaotic bleeding. ▶ Mirena is an alternative for this as it generally results in amenorrhoea so can be given constantly.Menopause - HRTMenopause - If not HRT, then what? ▶ Avoid vasomotor triggers - caffeine, hot drinks, alcohol ▶ Layer clothing and bedding ▶ Mindfulness or CBT ▶ Exercise ▶ Sleep apps ▶ Non-hormonal drugs - SSRI, SNRI (particularly venlafaxine), gabapentin, oxybutynin (can dry up sweats) ▶ Lubricant and vaginal moisturiserMenopause - Contraception ▶ HRT is not a contraceptive! ▶ Unless we are certain that the patient has had their final menstrual cycle, contraception is recommended alongside HRT until age 55 to avoid pregnancy ▶ >50yrs ▶ Merina - provides contraception and endometrial protection for HRT ▶ Combined hormonal contraception is not recommended after age 50 ▶ <50yrs ▶ Combined hormonal contraception can be used but without the hormone-free interval as this would result in a resurgence of menopausal symptomsMCQ Why are females more at risk of fractures in their 60’s than males? A - higher levels of testosterone in males prevent fractures B - females experience a significant decline in oestrogen during menopause C - men have denser bone quality than women D - females have a higher calcium intake than males E - oestrogen levels in men remain constant after age 40MCQ Why are females more at risk of fractures in their 60’s than males? A - higher levels of testosterone in males prevent fractures This is only partially true - testosterone in men does get converted to oestrogen providing some extra protection but this also occurs in post-menopausal women B - females experience a significant decline in oestrogen during menopause Menopause causes a sudden and significant drop in oestrogen levels, leading to rapid bone loss C - men have better bone quality than women Men generally have a larger peak bone mass in women but that is quantity not quality D - females have a higher calcium intake than males Low calcium levels does increase fracture risk but this is not relevant in this question E - oestrogen levels in men remain constant after age 40 Testosterone levels in men gradually declines after age 40 and so there is also a slow reduction in oestrogen levels in men and women. This decline is not as drastic as the one that occurs in post-menopausal women however.MCQ A 52-year-old woman presents to her GP with hot flushes, night sweats, and mood changes. Which hormonal change is most likely responsible for her symptoms A - decreased oestrogen levels B - increased progesterone levels C - increased testosterone levels D - decreased luteinizing hormone (LH) levels E - increased follicle-stimulating hormone (FSH) levelsMCQ A 52-year-old woman presents to her GP with hot flushes, night sweats, and mood changes. Which hormonal change is most likely responsible for her symptoms A - decreased oestrogen levels Oestrogen plays a critical role in thermoregulation, emotional stability, and other physiological processes that are disrupted when its levels drop B - increased progesterone levels Progesterone levels decrease during menopause C - increased testosterone levels Testosterone levels remain stable or decline slightly during menopause but they do not increase D - decreased luteinizing hormone (LH) levels LH levels increase during menopause due to lack of negative feedback from oestrogen E - increased follicle-stimulating hormone (FSH) levels FSH levels increase significantly during menopause due to low oestrogen levels but this is not what drives the symptoms of menopauseMCQ Which of the following is NOT a benefit of HRT? A - symptom control for vasomotor symptoms B - bone protection C - cardiovascular protection D - contraception E - improved quality of lifeMCQ Which of the following is NOT a benefit of HRT? A - symptom control for vasomotor symptoms B - bone protection C - cardiovascular protection D - contraception HRT is NOT contraception. Unless we are certain that the patient has had their final menstrual cycle, contraception is recommended alongside HRT until age 55 to avoid pregnancy E - improved quality of lifeQUESTIONS?Feedback Please take a minute now before you leave to fill in a quick feedback form!Sign 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