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Week 2 - Male Endocrinology Flashcards

1
Q

The 2 major functions of the testes

A
  • produce sperm - produce sufficient testosterone to develop & maintain male sexual function, body function & fertility
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2
Q

Testosterone secreted by which cells? & describe location & effects

A

Leydig cells Adrenals - small amounts - adjacent to seminiferous tubules in the testicle - androgenic [spermatogenesis, 2ary sex characteristics, accessory organs, adult male sex behaviour] & anabolic effects [stimulation of somatic growth - increased mm & bone density]

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3
Q

Leydig cells respond to which hormone?

A

Luteinizing hormone hCG

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4
Q

_____ is secreted by Leydig cells, negatively regulating ____ action - this could play a role in testosterone deficiency in stress response

A

Corticotropin-releasing hormone (CRH) is secreted by Leydig cells, negatively regulating LH action – this could play a role in testosterone deficiency in stress response

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5
Q

What is the action and site of action of CRH?

A

Site of Action: Anterior Pituitary Action: stimulates release of ACTH

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6
Q

______ reduces LH-stimulated processes in rat Leydig cell, which can contribute to _______ deficiency

A

Corticosterone reduces LH-stimulated processes in rat Leydig cell, which can contribute to testosterone deficiency

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7
Q

What enzyme converts T to dihydrotestosterone?

A

5a-reductase

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8
Q

T converts to _____ via aromatase

A

estradiol

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9
Q

cholesterol → _________ → 17-OH-_________ → DHEA (dehydroepiandrosterone) → androstenediol → Testosterone

A

cholesterol → pregnenolone → 17-OH-pregnenolone → DHEA (dehydroepiandrosterone) → androstenediol → Testosterone

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10
Q

cholesterol → pregnenolone → ___________ → 17-OH-_________ → androstenedione → estrone → _________

A

cholesterol → pregnenolone → progesterone → 17-OH-progesterone → androstenedione → estrone →​ estradiol

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11
Q

In humans, what is the relationship between androgens and cognitive performance?

A

In humans, rel’n between androgens and cognitive performance show mixed results (mood, schizophrenia, Alzheimer’s)

Androgens and estrogens have a neuroprotective effect, also associated with less beta amyloid plaque and increased neuron survival in Alzheimer’s

Alzheimer’s treated with testosterone showed improvement over a year

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12
Q

Most studies showing cognitive improvement are for ___________, but not for ________.

Improvements were in ________.

A

Most studies showing cognitive improvement are for hypogonadal men with testosterone therapy, but not for normal males

Improvements were in memory, spatial ability, executive function

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13
Q

What is the link between hypogonadism & osteoporosis?

A

Hypogonadism is a risk factor for hip fractures in men.

Men lose bone mass with age, and hypogonadism is one cause of male osteoporosis

In young men with acquired hypogonadism, testosterone replacement increases bone density

Effects of testosterone seem to be both from testosterone itself, as well as conversion to estrogen

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14
Q

define hypogonadism

A

ale hypogonadism is a condition in which the body doesn’t produce enough testosterone or has an impaired ability to produce sperm or both.

You may be born with male hypogonadism, or it can develop later in life from injury or infection. The effects depend on the cause and at what point in your life male hypogonadism occurs.

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15
Q

Low total testosterone is associated with:

(cardiovascular - 5 items)

A
  • Higher visceral obesity
  • Insulin resistance
  • Low HDL
  • High TG, LDL, TC
  • Increased aortic atherosclerosis risk independent of BMI, lipids, smoking, EtOH intake
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16
Q

Men with CVD have ______ total testosterone

A

Men with CVD have lower total testosterone

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17
Q

What are the effects we see with Testosterone therapy in CVD?

A

Can decrease Lp(a) (in normal and hypogonadal)

Can decrease fibrinogen and plasminogen activator inhibitor-1 (PAI-1) – more for normal males vs. hypogonadal

Can decrease body weight, leptin, insulin levels in hypogonadal

Overall, testosterone treatments have not yet proven to be beneficial on CVD

Nor any significant adverse cardiovascular effects either

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18
Q

What is the relationship between T and obesity, & why?

A
  • Free T inversely correlated w BMI
  • likely d/t increased aromatization of T to E in visceral (subcutaneous?) fat
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19
Q

_____ total testosterone associated with ______ DM risk, & vice versa

A

High total testosterone associated with decreased DM risk

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20
Q

Some studies show bioavailable testosterone is _______ correlated with Beck Depression Inventory scores.

A

Some studies show bioavailable testosterone is inversely correlated with Beck Depression Inventory scores.

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21
Q

Testosterone supplementation in normal men lead to ________ anger hostility scores, but ___ _______ in actual aggressive behaviour

A

Testosterone supplementation in normal men lead to higher anger hostility scores, but no increase in actual aggressive behaviour

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22
Q

Explain Luteinizing hormone

A
  • a hormone produced by gonadotroph cells in the anterior pituitary gland
  • In males, LH acts upon the Leydig cells of the testis and is regulated by GnRH. The Leydig cells produce testosterone (T) under the control of LH, which regulates the expression of the enzyme 17-β hydroxysteroid dehydrogenase that is used to convert androstenedione, the hormone produced by the gonads, to testosterone, an androgen that exerts both endocrine activity and intratesticular activity on spermatogenesis.
  • LH is released from the pituitary gland, and is controlled by pulses of gonadotropin-releasing hormone (GnRH). When T levels are low, GnRH is released by the hypothalamus, stimulating the pituitary gland to release LH. As the levels of T increase, it will act on the hypothalamus and pituitary through a negative feedback loop and inhibit the release of GnRH and LH consequently. Androgens (T, DHT) inhibit monoamine oxidase (MOA) in pineal, leading to increased melatonin and reduced LH & FSH by melatonin-induced increase of GnIH synthesis and secretion. T can also be aromatized into Estradiol (E2) in order to inhibit LH. E2 decreases pulse amplitude and responsiveness to GnRH from the hypothalamus onto the pituitary.
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23
Q

In males, ___ acts upon the Leydig cells of the testis and is regulated by _____

A

In males, LH acts upon the Leydig cells of the testis and is regulated by GnRH

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24
Q

When T levels are low, GnRH is released by the ________, stimulating the _________ to release LH.

A

When T levels are low, GnRH is released by the hypothalamus, stimulating the pituitary gland to release LH.

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25
In hypogonadal men, what is the effective of supplemented T?
In hypogonadal men, testosterone seems to increase libido, enjoyment, percent full erection, and satisfaction with erections Doesn’t seem to have the same response in normal men
26
Clinical Manifestations of Fetal Androgen Deficiency? (1 symptom, 6 signs)
- sxs: ambiguous genitalia - ss: ambiguous genitalia normal female genitalia microphalus (resembling clitoromegaly) Pseudovaginal perineoscrotal hypospadias bifid scrotum Cryptorchidism
27
Clinical Manifestations of Prepubertal Androgen Deficiency (8 symptoms, 12 signs)
**- sxs:** delayed puberty lack of sexual interest/desire (libido) reduced nighttime or morning spontaneous erections Breast enlargement and tenderness Reduced motivation & initiative Diminished strength & physical performance No ejaculate or ejaculation (spermarche) Inability to father children (infertility) **- ss:** eunuchoidism infantile genitalia small testes Lack of male hair pattern growth; no acne Disproportionately long arms & legs relative to height Pubertal fat distribution Poorly developed muscle mass High-pitched voice Reduced peak bone mass,osteopenia,or osteoporosis Gynecomastia Small prostate gland Aspermia, severe oligozoospermia oe azoospermia
28
Clinical Manifestations of Adult Androgen Deficiency (8 sxs, 8 ss)
**- sxs:** incomplete sexual development lack of libido reduced nighttime or morning spontaneous erections Breast enlargement/tenderness Infertility Height loss, hx of minimal-trauma fracture Hot flushes, sweats Reduced shaving frequency **- ss:** eunuchoidism Small or shrinking testes Loss of male hair (axillary or pubic hair) Gynecomastia Aspermia or azoospermia or severe oligozoospermia Low bone mineral density (osteopenia/porosis) Height loss; minimal-trauma or vertebral compression fracture Unexplained reduction in prostate size or PSA
29
What is the active metabolite of testosterone & what is the enzyme it is formed by?
Dihydrotestosterone Formed via 5-α reductase
30
Compared to T, what level of DHT is found in the body?
1/10 the levels of Testosterone
31
\_\_\_\_\_\_\_\_\_-receptor complex regulates ______ secretion and virilization of the _______ during male sexual differentiation and is probably responsible for sexual dimorphism of muscle development.
Testosterone-receptor complex regulates gonadotropin secretion and virilization of the wolffian ducts during male sexual differentiation and is probably responsible for sexual dimorphism of muscle development.
32
\_\_\_\_\_\_\_\_-receptor complex controls external virilization during embryogenesis and the development of _________ during puberty, including androgen-mediated hair growth and loss.
Dihydrotestosterone-receptor complex controls external virilization during embryogenesis and the development of most male secondary sexual characteristics during puberty, including androgen-mediated hair growth and loss.
33
Receptors are the same for testosterone and DHT; why have DHT?
- Uncertain: different functions, but lots of overlap too - DHT appears to have a greater affinity for the receptor, and thus may act as a type of signal amplifier - Potency reported as 2-10x higher than testosterone - Thus the use of 5-α reductase inhibitors in BPH treatments
34
What form of estrogen is predominantly found in men?
estradiol
35
Sources of estradiol in the body?
aromatization from testosterone (e.g. in adipose tissue) primarily, also direct secretion from testes, adrenal cortex
36
roles of estrogen in men? (7)
- closure of the epiphyses - acceleration of pubertal growth spurt - accrual & maintainence of bone density - influence on gonadotropin secretion - role in male sexual drive &/or potentiation - control of epididymal function - brain function
37
Estrogen in men may increase risk of \_\_\_\_
BPH
38
Acute ethanol ingestion can lower ______ levels and increases _____ in men
Acute ethanol ingestion can lower testosterone levels and increases LH
39
Chronic alcohol abuse can lead to hepatic cirrhosis and increase _______ and gynecomastia
Chronic alcohol abuse can lead to hepatic cirrhosis and increase estrogen and gynecomastia
40
Why don’t the normal amounts of estrogen cause gynecomastia?
Androgens appear to be weak anti-estrogens and block estrogen receptors
41
What is gynecomastia?
Abnormal breast tissue development in men (not adipose tissue) May be normal in neonates, puberty, and old age
42
incidence of gynecomastia?
Incidence of breasts – puberty up to 70%, and adult prevalence is about 34% (First Consult [2007])
43
dx of gynecomastia?
Dx via palpating the tissue, usually found around the nipple Check TSH, LH, testosterone, estradiol, and hCG
44
etiology of gynecomastia?
Usually idiopathic or drug-related
45
prognosis of gynecomastia?
Potentially reversible if present for less than one year, but changes may be irreversible after 1 yr
46
how to rule out breast cancer in a male?
mammogram
47
What is andropause & what is the age of onset?
Syndrome associated with decline in androgens that does not occur in all men, and the presentation varies. No definitive age of onset – can be as early as 4th decade of life (!!)
48
Sxs and ss of andropause?
Decreased potency and libido, decreased muscle strength, increased fatiguability Can include BPH and signs of feminization (e.g. gynecomastia) Reduction of bioavailable testosterone, DHT doesn’t change
49
What percentage of bioavailable T is free, and what percentage is weakly bound to albumin? And what is the rest bound to?
Free: ~2% bound to albumin: ~54% rest tightly bound to SHBG (sex hormone binding globulin; not available)
50
bioavailability of sex hormones is influenced by the level of \_\_\_\_\_.
SHBG
51
The relative binding affinity of various sex steroids for SHBG is \_\_\_\_\_\_ \> \_\_\_\_\_\_\_\_ \> androstenediol \> \_\_\_\_\_ \> \_\_\_\_\_\_\_. Androstenedione is not bound to SHBG, and is instead bound solely to \_\_\_\_\_\_\_.
The relative binding affinity of various sex steroids for SHBG is dihydrotestosterone (DHT) \> testosterone \> androstenediol \> estradiol \> estrone.[2] DHEA is weakly bound to SHBG as well, but DHEA-S is not.[2] Androstenedione is not bound to SHBG either, and is instead bound solely to albumin.
52
The circulating androgen concentration affects SHBG synthesis. Elevated testosterone causes SHBG synthesis to \_\_\_\_\_\_\_\_, while high estrogen __________ SHBG production.
The circulating androgen concentration affects SHBG synthesis. Elevated testosterone causes SHBG synthesis to decrease, while high estrogen stimulates SHBG production.
53
At what age does testosterone begin to drop about 1% per year?
40 yoa
54
Due to SHBG increases with age, bioavailable testosterone drops even more. What percentage per year?
Due to SHBG increases with age, bioavailable testosterone drops even more (2-3%/year)
55
SHBG can be decreased in? ## Footnote (5 conditions)
SHBG Can be decreased in: Hypothyroidism, acromegaly, Cushing’s disease, obesity, hyperprolactinemia Growth hormone decreases SHBG Often low SHBG seen in hirsutism, acne, PCOS
56
What herb may be a potent regulator of SHBG?
Urtica
57
SHBG can be increased in? (5 conditions)
Can be increased in: Hyperthyroidism, liver cirrhosis, estrogen dominance or low progesterone, during pregnancy and hormone therapy
58
7 hormones that are elevated in older men?
FSH LH Vasopressin Atrial natriuretic hormone Insulin PTH Leptin
59
9 hormones that are reduced in older men?
GH IGF-I Testosterone Renin Aldosterone T3 DHEA & DHEAS 1,25-(OH)2 Vitamin D 25-OH Vitamin D
60
6 hormones that remain at same level in older men as compared to younger adults
ACTH Cortisol Epinephrine TSH Thyroxine Glucagon
61
6 possible sxs of andropause
- decline in mm mass & strength assoc. w/reduced physical function & performance - decreased Bone Mineral Density - increased body fat - reduction in sexual activity & function, e.g. ED, lower libido - decline in vitality, energy, mood, cognitive function - decreased sleep quality
62
The most widely accepted parameters to establish the presence of hypogonadism is \_\_\_\_?
The most widely accepted parameters to establish the presence of hypogonadism is the measurement of serum total testosterone
63
Dx of testosterone deficiency?
Diagnosis rests on physical signs, symptoms, and laboratory values demonstrating symptomatic, inadequate testosterone levels. - measure serum total T - if low, repeat incl. SHBG to figure out free T
64
Why measure LH in hypogonadism?
Measuring LH will tell you if primary or secondary hypogonadism
65
Absolute CI to testosterone therapy?
- existing prostate or breast cancer; can potentiate!
66
Relative CIs to testosterone therapy? (3)
CHF, polycythemia, severe sleep apnea
67
If on T therapy, what physical exams recommend as f/u?
Recommended DRE + PSA every 3-4 months for 1st yr, then ev year, then ev 2 years
68
describe Phthalate syndrome
includes infertility, decreased sperm count, cryptorchidism, hypospadias, and other reproductive tract malformations
69
What does stress have to do with testosterone?
HPA axis Mediates cortisol; excess cortisol increases visceral adiposity, which leads to increased inflammation and cytokines High waist:hip decreases testosterone
70
What does sleep have to do with testosterone?
Sleep deprivation increases HPA axis hormones Peak testosterone levels coincide with rapid eye movement (REM) sleep onset (particularly older men, but also shown in young healthy men) Short sleep times of 5.5 hours per night were associated with weight gain, reduced oral glucose tolerance, and reduced insulin sensitivity
71
What does diet have to do with testosterone?
Remember low testosterone is closely associated with insulin resistance, metabolic syndrome, and type 2 diabetes Focus diet on limiting insulin resistance Reduce EtOH consumption Healthy weight management Adipose estrogen minimization
72
What does exercise have to do with testosterone?
In general, testosterone concentration is elevated directly following heavy resistance exercise in men Protocols high in volume, moderate to high in intensity, with easy short rest intervals and stress in a large muscle mass, tend to produce the greatest acute hormone elevations Work bigger muscle groups Total load volume may matter most E.g. 10 sets, 10 reps (~75% of 1 rep max weight) Don’t overtrain Caffeine prior to exercise
73
What food acts as a 5-alpha reductase inhibitor?
Soy acts as 5-alpha reductase inhibitor Also may act as phytoestrogen and prevent excessive DHT stimulation from more potent estrogens ## Footnote Shown to lower prostate cancer risk. **_Beta-sitosterols (major phytosterol in soy)_** Increased urinary flow, decreased residual volume in the bladder at 20 mg/d Also found in Serenoa, Secale, Pygeum, Urtica, rice bran, wheat germ, canola oil, pumpkin seed…
74
What is the major phytosterol in soy & what does it do?
**_Beta-sitosterols_** ## Footnote inhibit aromatase and 5α-reductase 60 mg bid; the dose can be lowered to 30 mg bid after symptoms improve 3.5-ounce serving of soybeans, tofu, or other soy food preparation provides approximately 90 mg of β-sitosterol A 1-ounce portion (about the size of the palm of the hand) equals approx 25 mg. A Cochrane Review found β-sitosterol improved urinary symptoms and flow measures but did not appear to reduce the size of the prostate gland.
75
What does zinc have to do with testosterone?
Important cofactor in many metabolic reactions within the body, and implicated in testicular development, sperm maturation, and testosterone synthesis Serum levels positively correlated with testosterone levels in men 36-60 yoa In group of infertile men with low T, Zn increased T, DHT, sperm counts In pts with kidney dz and ED, Zn improved ED Intestinal uptake of zinc is inhibited by estrogen Acts as 5α-reductase inhibitor Also inhibits binding of androgens to receptors in prostate Typical dose: 25-50 mg, but mindful of interaction with copper longterm (balance with 2mg/d if needed)
76
What does saw palmetto have to do with testosterone?
- serenoa repens Weak 5α-reductase inhibitor But may act more actively in reducing the number of estrogen and DHT receptors Also has anti-inflammatory effect on prostate Has β-sitosterol Reduces the inner prostatic epithelium but does not reduce the size of the gland Still, it improves symptom scores, nocturia, residual urine volume, and urinary flow in patients with BPH Found to be as effective as finasteride (Proscar) with fewer side effects. Dose: 160 mg bid; therapeutic benefit can take 8 weeks to appear.
77
Other than saw palmetto (serenoa repens), what are 4 herbs that are helpful in increasing T levels?
**Secale cereale (rye grass pollen)** Has β-sitosterol and some anti-inflammatory effects Typical dose:126 mg tid **Prunus africana (pygeum)** Has β-sitosterol and some anti-inflammatory effects Typical dose: 100-200 mg/d **Myomin** Combo of herbs; in vitro aromatase inhibitor **Eurycoma longifolia (Tongkat ali)**
78
What herb can we use to decrease T levels?
**Vitex agnus-castus** Regulates LH secretion from the anterior pituitary, and therefore potentially testosterone levels too Not many studies, but traditionally used in male acne, as well as monks to decrease libido May also be anti-proliferative to prostate (Actea racemosa – shows some anti prostate cancer effects in animal and in vitro studies)

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