W10 - PUBERTY AND MENOPAUSE Flashcards

1
Q

Define puberty. Explain the process of the attainment of fertility in males and females

A
  • Puberty is defined as the ability to successfully reproduce
    • Achievement of fertility
  • Puberty is a process that takes time, not a single event
  • Derived from the Latin pubscere which means “to be covered with hair”
    • Hair-growth around genitals, armpits and legs
  • Attainment of fertility has many definitions in females
    • Age of menarche - the first menstrual period
      • Definitive sign of onset of puberty - higher oestrogen levels in order to stimulate proliferation of endometrium and removal for shedding
      • Menarche does not mean first ovulation (months to two years later)
      • First few - low FSH and LH levels so follicles do not mature fully, but still produce enough oestrogen to build up endometrium and then low levels for shedding
    • Age of first ovulation
      • Difficult to observe (does not mean fertility)
        • Requires microscopic surgery, ultrasound, monitoring in order to tell
      • Still not indicative that an individual would be able to carry a pregnancy to term - not right ratio of progesterone and oestrogen to maintain a pregnancy
    • Age of dependable ovulation in which a female can support pregnancy without deleterious effects
      • Metabolic costs of pregnancy and lactation are high
      • Depends on reaching a threshold body size and condition
  • Attainment of fertility has many definitions in males
    • Age of first ejaculation
      • Definitive sign of onset of puberty
      • Ejaculation does not mean successful fertilisation (early ejaculate often azoospermic)
      • Seminal vesicle secretion - accessory glands are being stimulated by testosterone
    • Age when spermatozoa first appear in ejaculate
      • First sperm does not mean successful fertilisation (sperm-containing ejaculates initially oligozoospermic)
    • Age when ejaculate contains threshold number of spermatozoa - successful natural fertilisation
      • <15 million/mL is sub-fertile
    • 10-14 for boys (Onset) - first indication of puberty
      • Enlargement of testes and scrotum
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2
Q

Explain the changes in the hypothalamic-pituitary-gonadal axis during the onset of puberty

A
  • The onset of puberty is regulated by the hypothalamus
  • Depends on hypothalamic neurons producing sufficient quantities of GnRH to promote and support gametogenesis
  • Hypothalamus functionally different in males and females (absence of positive feedback in males)
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3
Q

Explain the significance of alpha-fetoprotein and the blood-brain barrier

A
  • Hypothalamus is inherently female
  • Males
    • Testosterone from foetal testis “defeminizes” the brain by inhibiting the surge centre
    • It Is oddly oestradiol that is responsible for this process
  • Females
    • Alpha-fetoprotein in foetus prevents oestradiol from crossing the blood-brain barrier
    • No internal oestradiol = Surge centre (hypothalamus) develops
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4
Q

Explain the changes in GnRH secretion before and after puberty

A
  • Before puberty
    • Males and females - pulses of low frequency and amplitude (tonic centre)
  • After puberty
    • Males and females - pulses of increased frequency and level (tonic)
    • Females only - with preovulatory burst (surge centre)
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5
Q

Explain why LH secretion differs between males and females

A
  • Males
    • LH secretion in men is of low amplitude with regular pulses (every 2-6 hours)
  • Females
    • There is a surge every cycle separated by low amplitude pulses
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6
Q

Explain the function of testosterone

A
  • Responsible for spermatogenesis and characteristics that define the masculine body
  • Production increases rapidly during puberty to decrease responsiveness of the hypothalamus-pituitary axis to negative feedback
  • Starts the development of sexual characteristics
    • Development of male primary sexual characteristics
      • Penis, scrotum and testes increase in size (8-fold increase by 20 years)
      • Prostate gland
      • Seminal vesicle
      • Male genital ducts (Including epididymis and vas deferens)
    • Development of male secondary sexual characteristics
      • Body hair - over abdomen, face and chest
      • Baldness - decrease growth of hair on top of head
      • Voice - hypertrophy of laryngeal mucosa and enlargement of larynx
      • Skin - increased thickness, increased sebaceous gland secretions and acne
      • Muscles - protein formation and muscle development
      • Bone - increase bone matrix and Ca++ retention
      • Metabolism - increase basal metabolism
      • Behaviour - promotes sex drive (libido) and aggressiveness
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7
Q

Explain the functions of oestrogen

A
  • Responsible for the onset of ovarian and uterine cycles (triggers ovulation and endometrial proliferation) as well as characteristics that define the feminine body
  • Production increases 20-fold during puberty due to decreased responsiveness to the hypothalamic-pituitary axis to negative feedback
  • Stimulates the development of sexual characteristics
    • Development of female primary sexual characteristics
      • Vagina, uterus, oviducts and external genitalia enlarge
      • Uterus and oviducts exhibit enhanced motility
      • Vaginal mucosa thickens
      • Stimulates “watery” cervical mucus (facilitates sperm transport)
    • Development of female secondary sexual characteristics
      • Breasts - development of stroma and duct system
      • Bone - promote long bone growth, widening of pelvis, Ca++ retention and eventual epiphyseal closure
      • Fat - deposition of subcutaneous fat (breast and hips)
      • Metabolism - increased HDL (high-density lipoproteins) and decreased LDL (low-density lipoproteins) in blood
      • Skin - increased hydration (soft and smooth texture)
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8
Q

How do GnRH neurons acquire the ability to release GnRH in high frequency pulses?

A
  • Onset of puberty is not limited by gonads or anterior pituitary
    • Exogenous pulsatile GnRH treatment in prepubertal primates causes LH and FSH release
    • Exogenous FSH and LH treatment causes follicles to grow and produce oestrogens in prepubertal ovaries
  • Puberty depends on the release of sufficient quantities of GnRH from the hypothalamus
    • This process occurs gradually
  • Before puberty
    • Tonic centre is highly sensitive to negative feedback by low levels of oestrogens and testosterone from the ovaries or testes of females and males respectively
    • The surge centre is not yet responsive to positive feedback by oestrogen
  • During pubertal transition
    • Sensitivity begins to decline and increasing amounts of GnRH are produced by the tonic centre
    • Need more oestrogen and testosterone to suppress GnRH until a new equilibrium is established
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9
Q

What causes the tonic centre to lose sensitivity to negative feedback?

A
  • Pregnancy and lactation exert a high metabolic cost
  • A certain degree of fat reserves are needed before the brain “allocates” energy to initiate reproductive processes
  • However, “fatness” alone does not promote puberty
    • Young girls can be obese but not peripubertal
    • Also depends on reaching a threshold body size/condition
  • Fatness and the underlying metabolic signals are best understood in the female
  • The loss of sensitivity and initiation of high frequency GnRH pulses may be influenced by concentration of glucose, leptin or fatty acids in blood
  • Possible influence of metabolic signals on GnRH neurons
    • Blood glucose levels (another indicator of metabolic status) might stimulate glucose sensing neurons that in turn stimulate GnRH neurons
    • Adipocytes produce leptin that enter the blood - may stimulate neuropeptide Y neurons or directly stimulate GnRH neurons
    • Blood leptin reflects nutritional status because the greater amount of fat, the greater the amount of leptin
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10
Q

Explain the trend towards earlier onset of puberty in girls

A
  • Related to improved quality and quantity of food but critical weight (approximately 47kg) must be obtained
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11
Q

What is menopause?

A
  • The permanent cessation of menstruation that results from the loss of ovarian follicular function
    • Diagnosed retrospectively after 12 months amenorrhea
    • Functionally equivalent to oestrogen withdrawal syndrome
  • From the Greek
    • “Meno” means month
    • “Pause” means cessation/stop
  • Menopause is a natural stage in a woman’s life
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12
Q

Explain the physiology of menopause

A
  • Loss of ovarian responsiveness to gonadotrophins due to decline in follicles
  • Ovarian oestrogen, inhibin and progesterone production falls
  • Serum FSH and LH levels slowly rise
  • Menstrual cycle length is variable then decreases as follicular phase shortens
  • Ultimately ovulation and menstruation cease entirely
  • Postmenopausal ovary is small and devoid of follicles
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13
Q

Explain the timing of menopause

A
  • Average age
    • 51 years
  • Normal range
    • 45 to 55 years
  • Genetically determined
    • Maternal menopausal age predicts age in daughter
  • Smokers enter menopause earlier
  • Preceded by climacteric or perimenopause (Reproductive transition period)
    • Generally evident mid-late 40s (as early as 35)
    • Lasts several years, 10 years, or longer
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14
Q

What are some symptoms and concerns associated with the menopausal transition?

A
  • Menstrual irregularities
    • Cycle length varies, shortens then stops
  • Hot flushes (75%)
    • Sudden intense feelings of heat and profuse sweating, night sweats (may last 1 to 5 years)
  • Mood disturbances
    • Headaches, irritability, insomnia, depression
  • Atrophy of reproductive tract and breasts
    • Decrease in size and internal secretions (vagina more prone to infections and pain during intercourse)
    • Urinary frequency, urgency and incontinence
  • Bone changes
    • Increased bone resorption and diminished formation results in thin fragile bones
  • Cardiovascular changes
    • Increase in low density lipoprotein (LDL), decrease in high density lipoprotein (HDL) and weight gain
  • Concerns
    • Increased risk of cardiovascular disease
    • Increase risk of osteoporosis
      • 50% vertebrae and 25% hip fractures by age 80
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15
Q

What are some underlying causes of menopause?

A
  • Menopause = Oestrogen withdrawal syndrome
    • Developing follicles are a source of ovarian oestrogens
    • Primary cause - depletion of finite pool of follicles
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16
Q

Explain the endocrine changes during menopause

A
  • Before
    • Oestrogens are elevated, FSH and LH are low
  • After
    • Oestrogens drop, FSH and LH increase
17
Q

Explain some additional causes of menopause

A
  • Age-related changes in central nervous system and hypothalamic-pituitary unit may also contribute to menopause
  • Circadian oscillator changes
    • Decreased nocturnal melatonin secretion and alters sleep
    • Decreased sensitivity of hypothalamic-pituitary axis to steroids (Negative feedback)
      • Causes a gradual rise in LH and FSH prior to oestrogen decline
    • Resetting the gonadostat
      • Humans - lower melatonin - disequilibrium in GnRH; ovaries cannot keep up with the stimulating follicles to grow because store is low
18
Q

Explain the changes in folliculogenesis during menopause

A
  • Increased FSH and LH (even before menopause due to decreased sensitivity to negative feedback)
  • Gradual increase in GnRH and LH/FSH
  • Leads to ovarian hyperstimulation
    • FSH recruits more follicles and accelerates maturation
      • Causes shorter follicular phases and shorter ovarian cycles
  • Multiple recruited follicles - higher oestrogen
    • Super stimulates follicles
    • Multiple ovulations - twins/triplets in later reproductive years
  • Ultimately results in accelerated depletion of ovarian follicles
    • Accelerates progression towards menopause
  • Depleted follicle pool - decreased follicle cohorts recruited and decreased oestrogens
    • Anovulation (higher oestrogen needed for LH surge)
  • Persistent follicles/oestrogens = long follicular phase/cycle and heavy menses
  • Ultimately results in very low follicles - low oestrogen, anovulation and light to no menses
  • Follicle recruitment and oestrogen levels highly variable during perimenopause = variable cycle length, ovulation and menses
19
Q

Explain treatment options for menopause in particular hormonal replacement therapy

A
  • Oestrogen treatment
    • Benefits
      • Can effectively treat hot flushes, osteoporosis, genital atrophy and possibly mood disturbances
      • Alzheimer’s, osteoarthritis, colon cancer, tooth loss and skin ageing may also decrease
      • There is no reduction in cardiovascular disease
    • Risks
      • Increased risk of endometrial cancer (Unless combined with progestagen) due to proliferation of endometrial cells
      • Other potentially serious side effects
20
Q

What are some side-effects associated with hormone replacement therapy? Suggest some recommendations and medical alternatives

A
  • Mostly affected postmenopausal women over 60
  • Increased risk of
    • Coronary heart disease
    • Stroke
    • Breast cancer
    • Venous thromboembolism (blood clots)
      • Particularly long-term treatment and older women
  • Recommendation
    • Only during perimenopausal period to alleviate symptoms (particularly hot flushes)
      • Lowest dose for the shortest effective time (NIH 2017)
  • Medical alternatives
    • Raloxifene - selective oestrogen receptor modulator (SERM)
      • Treats/prevents osteoporosis
      • Positively alters lipid ratio
      • Alleviates hot flushes
      • Reduces risk of breast cancer
      • Does not stimulate endometrial proliferation
21
Q

Describe some “natural” or herbal therapy for the treatment of menopause

A
  • Botanicals
    • Phytoestrogens from soybeans, chickpeas and wild yam
    • Black cohosh
    • St. John’s wort
    • Evening primrose oil
  • May provide short-term alleviation from hot flushes or depression but limited scientific proof
  • May interfere with current medications
22
Q

How might a woman alleviate symptoms associated with menopause?

A
  • Hot flushes
    • Avoid trigger factors
    • Dress in layers
    • Regular exercise
  • Sleep disturbances
    • Develop a sleep routine
    • Avoid caffeine after midday
    • Regular exercise
  • Bone loss/fracture
    • Avoid active lifestyle
    • Calcium supplementation (up to 1,500mg)
    • Vitamin D from sunlight and fortified milk
    • Regular checks of bone mineral density with general practitioner
    • Avoid falls (good posture avoid bending and lifting)
  • Heart
    • Reduce risk factors (excess weight, high cholesterol, high-fat diet, etc)
    • Regular exercise
    • Avoid smoking
23
Q

Explain the rationale for hormone replacement therapy

A
  • Request hormone replacement therapy
    • Risk of osteoporosis
    • Based on symptoms
      • Vaginal dryness, hot flushes, mood swings
  • Refuse hormone replacement therapy
    • Have not been pregnant
      • Breast has not finished final development, so someone who has not been pregnant has a higher chance of it being mutated
    • Active liver disease
    • Thromboembolic disorders
    • Breast/endometrial cancer
    • Chronic liver disease
    • Familial breast cancer