Puberty & Menopause Synthesis Session PDF

MD1020 Reproduction – Week 10 Assoc. Prof. Damien Paris [email protected]  Reiterate learning objectives – Week 10  Review selected problems/questions from GLS  puberty  menopause & endocrine changes  hormone replacement therapy  Describe the physiological & endocrine changes of male...

MD1020 Reproduction – Week 10 Assoc. Prof. Damien Paris [email protected]  Reiterate learning objectives – Week 10  Review selected problems/questions from GLS  puberty  menopause & endocrine changes  hormone replacement therapy  Describe the physiological & endocrine changes of males & females to puberty  Appreciate the actions of testosterone & oestrogen on primary & secondary sex characteristics of males & females  Describe the major signs & symptoms of menopause  Explain the underlying physiological & endocrine changes that cause menopause  Describe the rationale for using or refusing hormone replacement therapy to mitigate some of these effects Clarification: 1. What is one of the earliest changes that indicates the onset of puberty in boys? In girls?? 2. What is the normal age range for these initial changes? Definitions provided in lecture relate to ‘attainment of fertility’  boys: growth of testes & scrotum (typically ~10, range: 8 to 14 years)  girls: budding of breasts (typically ~10, range: 8 to 13 years)  source: Marieb & Hoehn 2013 (p.1058) Jones & Lopez 2006 (Table 6-1 & 6-3) Jones & Lopez 2006 6. If the hypothalamus can function during childhood, based on current thought, where do these maturational changes take place and what other signalling molecules might be involved??  central brain areas: ‘maturation’ of limbic system at puberty thought to lift initial inhibition on hypothalamus  nutritional status (♀): ↑ conc. leptin, fatty acids or glucose in blood = sufficient fat reserves then promote ↑ hypothalamic activity  source: Jones & Lopez (2006); Hall (2016) http://www. antranik.org Others? 2. What would you predict to be the relative postmenopausal levels of FSH and LH compared to the time before menopause? Explain based on changes in feedback due to changes in follicle number.  depleted follicle pool = decreased ovarian function  few follicles = low oestrogen, inhibin & progesterone (no ovulation = no CL)  low steroids = –ve feedback on H-P axis removed = high LH & FSH atresia postmenopause low oestrogen inhibin progesterone Senger 2005 Melmed et al. 2011 Johnson 2007 3. Briefly describe the changes in follicle recruitment, ovulation, hormones & menses during the perimenopause.  remember before menopause FSH (& LH) already start to rise!!  due to ↓ sensitivity of H-P axis to –ve feedback  gradual ↑ GnRH = gradual ↑ FSH & LH Jones & Lopez 2006  Ovaries:  ↑ FSH recruits more follicles = ↑ oestrogen & accelerated ovulation = shorter follicular phase = shorter ovarian cycle with menses  multiple recruited follicles per cycle  ↑ FSH & oestrogen can ‘super-stimulate’ follicles = multiple ovulation = twins/triplets in later reproductive years Ultimately results in accelerated depletion of ovarian follicles = accelerated progression toward menopause McCance & Huether 2006  depleted follicle pool = ↓ follicle cohorts recruited = lower oestrogen  lower oestrogen = anovulation (high oestrogen needed for LH surge)  persistent follicles/oestrogen = long follicular phase/cycle & heavy menses  ultimately v. few follicles = v. low oestrogen = anovulation = light then no menses = no cycle = menopause Follicle recruitment & oestrogen levels highly variable during perimenopause = variable cycle length, ovulation & menstrual severity McCance & Huether 2006  short answer: Age-related changes in CNS??  hypothesis:  Circadian oscillator change = ↓ melatonin = disrupted sleep  ↓ melatonin = ↓ sensitivity of H-P axis to –ve feedback how?  Melatonin secretion is detected by hypothalamus in some animals & leads to alterations in GnRH secretion:  Short day breeders: ↑ melatonin = ↑ GnRH = ↑ FSH/LH  Long day breeders: ↓ melatonin = ↑ GnRH = ↑ FSH/LH similar to human menopause?? Others?  Lobo Nat. Rev. Endo (2017):  HRT effective: hot flushes, osteoporosis, ↓ endometrial cancer (E2+P4) but ↑ risk stroke, VTE, breast cancer (slight), coronary heart disease  healthy ♀ <60 years: ↓ coronary heart disease, no risk stroke, ↓ mortality  advocates: oestrogen or conjugated equine oestrogen alone (but ↑ risk of endometrial cancer)  NIH Nat. Inst. Aging (2017):  HRT effective: hot flushes, bone loss, vaginal dryness but ↑ risk heart attack, VTE, stroke, breast cancer, gall bladder disease, dementia (♀ >60)  healthy ♀ <60 years: less risks & more potential benefits  HRT at the lowest dose, for the shortest time it remains effective  studies needed to evaluate long-term safety of newer treatments ?  Marjoribanks et al. Cochrane DB. Sys. Rev. (2017):  22 double-blind random controlled trials till Sep 2016 (43,637 ♀ most >60)  combined HRT: ↑ risk heart attack, VTE, stroke, breast cancer, gall bladder disease, lung cancer death, dementia  ♀ <60 years: slight risk VTE but data insufficient to determine long term risk of HRT  Conclusions:  lean healthy non-smoking women can continue to use COCs through the perimenopause until menopause (Melmed et al. 2016; Lobo 2017)  more studies needed to determine long term risk/benefit of HRT during perimenopause (Marjoribanks et al. 2017)  lowest dose for shortest effective time during perimenopause to alleviate symptoms (particularly hot flushes)(NIH 2017)  studies needed to evaluate long-term safety of newer treatments