Menopause and Andropause physiology

1. THE PHYSIOLOGY OF
MENOPAUSE AND ANDROPAUSE
Group 3 members: Dr. Mandeq Adow
Dr. Yvonne Mukiri
Dr. Faith Mwikali
Dr. Robert Maina
Dr. Sarah Kamau

2. Outline
 Introduction
 Overview of ovarian physiology
 Hormonal changes in the peri-menopause and menopause
 Symptoms and diagnosis of menopause
 Treatment options
 Physiology of andropause
 Principle of management of andropause

3. Introduction
 The climacteric is the phase of the aging process in which a woman passes from
reproductive to nonreproductive capability (generally age 40–55 years).
 This phase covers 5-10 years on either side of menopause.
 Perimenopause is the part of the climacteric where the menstrual cycle is likely to
be irregular.
 The perimenopause normally lasts about 4 years and is marked by altered ovarian
function

4. Menopause
 Menopause is defined as permanent cessation of menstruation
following the characteristic altered ovarian function
 Cannot be diagnosed until there is cessation of menstrual bleeding for 12
consecutive months without any other pathology.
 Age of menopause ranges from 45-55 years with an average of 50 years.
 One of the most powerful predictors of age at menopause is family
history, with twin studies estimating that a remarkable 44–85% of the
variance in age at natural menopause is heritable.
 Is not affected by age at menarche, parity, use of oral contraceptives or age
at last pregnancy.

5. Early menopause
 Has been associated with factors that accelerate follicle loss through
damage to the oocyte and/or dividing granulosa cells such as
smoking, infection , chemotherapy (especially alkylating agents),
radiation.
 Also results from surgical procedures that impair ovarian blood
supply, tumors, or surgical removal of the ovaries.
 Premature menopause is defined as menopause occurring <40 years
of age.

6. Delayed menopause
 Failure of menopause to occur beyond the age of 55 years
 Causes include:
 Constitutional
 Estrogen secreting ovarian tumor
 Uterine fibroids
 Diabetes mellitus can affect ovarian ageing, potentially causing women
with type 1 diabetes mellitus and early-onset T2DM to experience
menopause earlier than women without diabetes mellitus
 Endometrial hyperplasia/ endometrial carcinoma

7. Ovarian Physiology-Overview
 Primordial germ cells migrate to the genital ridge by 5 weeks of
gestation. Successive mitotic cellular divisions form oogonia, which
in turn give rise to oocytes.
 There are approximately 7 million oogonia present in the fetus at 20
weeks in-utero
 Their numbers gradually decline, leaving 2 million at birth and only
300,000 at puberty. This reduction continues until menopause. The
oogonia are reduced by atresia (the primary cause of loss) and
ovulation (400–500 per lifetime).

8. Normal menstrual physiology-overview
 Normal menstrual cycle function requires tightly integrated interactions
between the hypothalamus, pituitary and ovary while the endometrium
serves as a gonadal steroid end organ
 At the beginning of each cycle, increasing levels of FSH are necessary for
recruitment of a new cohort of follicles while restraint of FSH is required
to ensure that only a single follicle reaches the preovulatory stage
 Estradiol secretion from developing follicles contributes to the negative
feedback control of FSH, acting at both the hypothalamus and, to a lesser
degree, the pituitary.
 Ovarian secretion of inhibin B and inhibin A provide an additional level of
control through selective inhibition of FSH at the pituitary.

9. Normal menstrual physiology-overview
 In the late follicular phase, rising levels of estradiol result in
generation of the preovulatory LH surge that is necessary for
ovulation.
 In the luteal phase, progesterone secretion from the corpus luteum is
maintained by LH secretion and inhibits GnRH pulse frequency.
 Increased hypothalamic GnRH secretion, made possible by the loss
of progesterone in the late luteal phase, is also necessary during the
luteal-follicular transition to achieve levels of FSH that are adequate
for the next wave of follicular recruitment.

10. Perimenopause
 Ovarian aging is marked by a diminishing response or sensitivity of the
ovaries and oocytes to gonadotropins.
 As a result effective folliculogenesis is impaired leading to a fall in serum
estradiol levels to about 10-20pg/ml from a previous 50-300pg/ml before
menopause.
 This results in reduced negative feedback effect on the HPO axis with
resultant increase in FSH levels
 There is also a reduction in inhibin levels(a peptide secreted by the
granulosa cells of the ovarian follicle) resulting in further increase in FSH
levels. Inhibin B plays an extremely important role as a gonadal feedback
modulator of FSH secretion in early ovarian aging with declining levels of
inhibin B associated with increasing FSH

11. Perimenopause
There is shortening of the mean cycle length due to
shortening of the follicular phase; the luteal phase remains
unchanged.
Ovulation may or may not occur because the maturation of
follicles becomes irregular. Anovulation, oligo-ovulation
and corpus luteum insufficiency that typically occur in this
period may result in endometrial hyperplasia as a result of
sustained levels of unopposed estrogen in some women.

12. Hormonal changes- Premenopause
 Rise in FSH especially during the early follicular phase
 LH levels unchanged
 Progesterone levels unchanged
 Lower estradiol levels
 The elevated FSH levels may stimulate the release of bursts of estradiol from the
residual follicles, causing estrogen stimulation of the endometrium, which in the
absence of regular progesterone secretion results in irregular bleeding.

13. Hormonal changes-Menopause
Estrogen and progesterone materially decrease at, or
before, the time of menopause as well as when the ovaries
are removed or sufficiently altered to cease physiologic
functioning.
GH and DHEAS levels also decrease at menopause
AMH is present in the ovary until menopause. Can be
used as a reliable marker of ovulatory function and
ovarian reserve.

14. Estrogen
 Ovarian secretion of estradiol falls significantly
 Post menopausal estradiol levels 10-20pg/ml
 The residual estradiol is produced indirectly by the adrenal glands.
 Estrone and testosterone converted to estradiol in the peripheral
tissues
 Peripheral aromatization of adrenal androstenedione to estrone
accounts for most of the estrone production
 Serum estrone levels are 30-70pg/ml

15. Progesterone
Because progesterone is produced by the corpus luteum,
postmenopausal progesterone levels are only 30% of those
seen in ovulating women.
The adrenal gland is presumed to be the source of the
small amount of progesterone in postmenopausal women.

16. Androgens
 Androstenedione is the predominant androgen secreted by developing
follicles. With cessation of follicular development in post-menopausal
women, androstenedione levels fall by 50%.
 The ovary secretes only 20% of androstenedione after menopause
 DHEA and DHEAS are produced primarily by the adrenals. Only about
25% by the ovary
 Both DHEA and DHEAS fall with aging by 60% and 80% respectively
 Post menopausal testosterone secretion falls by less than a third, often
resulting in slight virilization (e.g. facial hair and deepening of the voice)
due to the relative absence of estradiol and progesterone

18. Gonadotropins
 Reproductive age levels of LH and FSH= 4-30mIU/ml
 Pre-ovulatory surge >100mIU/ml and >50mIU/ml respectively
 Post menopausal, both >100mIU/ml
 Both demonstrate pulsatile bursts every 1–2 h, thought to be
secondary to pituitary response to hypothalamic release of
gonadotropin-releasing hormone (GnRH).
 Low estrogen levels increase pituitary sensitivity to GnRH.
 Ultimately , the levels of GnRH, LH and FSH fall along with the
decline of estrogens

19. Diagnosis of menopause
 1. cessation of menstruation for 12 consecutive months
2. appearance of menopausal symptoms
3. vaginal cytology maturation index of at least 10/85/5
4. serum estradiol <20pg/ml
5. serum FSH and LH >40 mIU/ml(three values at a
week’s interval)

20. Organ Specific Changes

21. Uterus
 Both the duration and flow of menstrual blood gradually diminish prior to the menopause
until only spotting is followed by cessation. On rare occasion, abrupt cessation occurs.
 In some women, vaginal bleeding will be heavier or more frequent, occasionally with
intermenstrual bleeding.
 The uterus shrinks, ratio of the corpus: cervix reverts to 1:1(previously 2:1 in the
reproductive age)
 The endometrium becomes thin and atrophic. Important considerations when assessing
endometrial thickness include: post-menopausal vaginal bleeding, tamoxifen therapy and
HRT
 For women with post-menopausal bleeding, the risk of carcinoma is approx. 7% if
endometrial thickness is > 5mm and 0.07% if <5mm

22. Uterus
 The cervix contracts in size and there is reduction in secretion of cervical
mucus
 Endometrial biopsy may show tissue changes ranging from a scanty
basal atrophic pattern to a moderately proliferative pattern. When
glandular hyperplasia is present, excessive estrogenic stimulation is
occurring and further investigation is necessary

23. Clinical Implications
 An enlarged uterus( corpus: cervix ratio >1:1) should raise
suspicion for benign or malignant uterine tumours
 75% of post-menopausal lower abdominal masses are benign while
25% are malignant in nature
 Common uterine tumours in post-menopausal women include
myomas, adenomyoma, endometrial carcinoma and uterine sarcoma
 Persistence of uterine myomas or adenomyomas points to estrogen
excess as these tumors tend to regress with estrogen deficiency in
post-menopausal women.

24. Vagina
 Atrophic changes occur due to fall in estrogen levels
- Result in thinning of the vaginal epithelium and easy bleeding with minimal
trauma.
- Vaginal rugae gradually disappears
- With further thinning of the epithelium and disappearance of the capillary bed,
eventually appears pale, shiny and smooth.
- The vaginal pH rises; lactobacilli are absent

26. Vaginal cytology and the maturation index

27. Vaginal cytology and the maturation index

28. Clinical implications
 These changes due to estrogen deficiency predispose the post-
menopausal woman to bacterial infections.
 In addition cervical cancer, endometrial cancer with pyometra,
cancer or infection of the fallopian tube may present with abnormal
vaginal discharge.
 Post-menopausal women with vaginal discharge must be evaluated
for malignancy.

29. Vulva
The labia become flattened
Scanty pubic hair
There is narrowing of the introitus post-menopausally

30. Fallopian tubes and Ovaries
• Muscle coat becomes thinner
• Cilia disappear
• Plicae become less prominent
• The ovaries also diminish significantly in size
• There is thinning of the cortex and an increase in medullary components
and stromal cells
• A palpable ovary in a post-menopausal woman is to be considered
neoplastic until otherwise proven.

31. Pelvic floor
 With estrogen deficiency comes progressive loss of pelvic tissue
tone which may result in enterocele, rectocele, cystourethrocele and
uterine prolapse.
 Treatment may be conservative with use of pelvic floor exercises
and vaginal pessaries or surgical depending on degree of prolapse

32. Urinary tract
Estrogen maintains the epithelium of the bladder and urethra.
Hence, estrogen deficiency causes atrophic cystitis and urethritis,
characterized by urgency and frequency without dysuria or pyuria.
Urethral tone decreases, occasionally allowing the meatus to protrude
(a reddened caruncle).

33. Breasts
 Breasts decrease in size and become less dense
(glandular tissue is replaced by fatty tissue)
 Nipples reduce in size

34. Skin and Hair Changes
 Estrogen receptors are present in skin, especially of the face, thigh,
and breasts
 With aging, the skin becomes thinner, with a loss of elasticity
leading to wrinkling.
 A characteristic ‘purse string’ wrinkling around the mouth and ‘crow
feet’ wrinkling around the eyes is seen.

35. Vasomotor episodes(hot flushes)
 Occur in 75% of women who have lost ovarian function
 Attributable to estrogen withdrawal rather than absence of estrogen
 Characterized by a feeling of heat experienced usually in the face,
immediately followed by profuse sweating. Some report palpitations,
vertigo, weakness, fatigue, or a feeling of faintness.
 The physiologic changes are perspiration and cutaneous vasodilatation
which coincide with GnRH pulses with increased serum LH levels
 Frequency ranges from 1-2 per hour to 1-2 per week
 Average duration approximately 4 minutes
 Can cause sleep disturbances with resultant fatigue, irritability, anxiety
and memory loss

36. Cardiovascular system
 The risk of heart disease has been shown to increase in women above
the age of 55, and to decrease with estrogen replacement therapy
 Estrogen increases HDL(esp. HDL 2), decreases LDL and total
cholesterol thereby preventing cardiovascular disease
 Also has anti-oxidant and anticoagulant properties that prevent
thrombosis and atherosclerosis.
 It prevents platelet and macrophage aggregation at the vascular intima
and stimulates vasodilatation by stimulation the release of NO and
PGI2 from the vascular endothelium
 Although menopause has not been shown to have an effect on blood
pressure, replacement estrogens increase both systolic and diastolic
blood pressure.

37. Osteoporosis
Osteoporosis is a systemic skeletal disease characterized by low
bone mass and microarchitectural deterioration of bone tissue,
with a consequent increase in bone fragility and susceptibility to
fracture
A useful generalization is that after menopause 3%-5% of BMD is
lost per year for the first 5 years and 1% per year thereafter.
Osteopenia is a t-score between -1 to -2.5 on DEXA scan whereas
values below -2.5 SD are diagnostic for osteoporosis(WHO)

38. Why does osteoporosis occur ?
 Estrogen;
i. Prevents osteoclastic activity and inhibits release of interleukin 1
ii. Increases absorption of calcium from the gut
iii. Stimulates calcitonin release from the C cells of the thyroid
 The bone loss is the result of bone resorption exceeding bone formation, with a
calcium loss of approximately 15 mg/d between 50 and 70 years of age (net loss
100 g).
 Trabecular bone loss (50%) is greater than cortical bone loss(5%)
 Estrogen replacement therapy results in decreased bone resorption and
decreased bone calcium loss

39. Risk factors
Estrogen deficiency
Sedentary lifestyle
Smoking
Excessive alcohol use
Excessive caffeine intake
Familial predisposition

40. Type 1 osteoporosis
 Osteoporosis due to:
 estrogen deficiency,
 age,
 nutritional deficiencies(calcium and vit D)
 hereditary causes

41. Type 2 osteoporosis
Medications adversely influencing bone mass include:
glucocorticoids, thyroxine, and heparin.
Diseases associated with decreased bone mass : multiple myeloma,
osteitis deformans (Paget’s disease of bone), metastatic cancer, or
hyperparathyroidism.
These maybe differentiated by serum calcium, phosphorus, and
alkaline phosphatase levels.
Occasionally, 24-h urinary calcium, parathyroid hormone, or serum
protein electrophoresis will also be useful.

42. Osteoporosis and fracture
 Loss of BMD occurs primarily in trabecular bone of the vertebrae
and distal radius
 Fractures typically involve the vertebral bodies, neck of femur and
distal radius(Colle’ s fracture)
 Osteoporosis may lead to back pain, loss of height and kyphosis

43. Psychological changes and dementia
 Anxiety, headache, insomnia, irritability , dementia and depression increase
during the climacteric
 These are aggravated by hot flushes occurring during the night
 Estrogen protects against dementia by enhancing opioid neurotransmitter activity
in the brain thus preserving memory.
 The incidence of severe psychiatric illness is not increased by menopause, but
estrogen therapy may improve the emotional state by relieving hot flushes,
insomnia, or vaginal atrophy.

44. Postmenopausal estrogen excess
1. Increased production e.g. due to androgenic or estrogenic tumours
of the ovary, adrenal neoplasms and increased peripheral
aromatization associated with obesity, hyperthyroidism or liver
disease.
2. Decreased degradation due to impaired liver function
3. Exogenous estrogen intake

45. Management
1. Prevention
Iatrogenic causes of menopause such as bilateral salpingo-
oophorectomy and radiation exposure may be preventable
2. Counseling
Serves to allay anxiety and reduce incidence of depression
Helps the woman to gain an understanding of the physiological events
occurring in her body.

46. Non-hormonal Treatment
1. Lifestyle modification-physical activity, smoking cessation, reducing intake of
alcohol and caffeine, tapering or withdrawing medications that cause bone loss
2. Supplementary calcium- 1-1.5g daily
3. Dietary-soy protein effective in reducing vasomotor symptoms
4. Bisphosphonates-alendronate is most potent. Ibandronate and zolendronic acid
have less side effects. Alendronate 10 mg PO qd mane,30 mins before anything
else by mouth. Treatment for 3 years has-been demonstrated to increase (6%–
9%) bone mass. Alendronate has a half-life of >10 years, but may cause
abdominal pain, musculoskeletal pain, and upper GI bleeding.

47. Non-hormonal Treatment
5. Vitamin D- 1500-2000 IU/day given alongside calcium supplementation
reduces osteoporosis and fracture risk.
6. Fluoride increases bone matrix and prevents osteoporosis. Given at a
dose of 1mg/kg for short-term use. Brittle bones may be a side effect of
sustained use.
7. Calcitonin therapy with calcium and vitamin D inhibits bone resorption.
It is given as a nasal spray-200IU- daily or SC 50-100 IU daily

48. Non-hormonal Treatment
8. Selective Estrogen Receptor Modulators(SERMs)
Raloxifene is the drug of choice.
Acts as an estrogen agonist both in bone and the liver(decreases LDL
and increases HDL 2)
Inhibits the estrogen receptors at the breast and endometrium, reducing
the risk of breast and endometrial cancer.
9. Paroxetine(SSRI)-useful in reducing the frequency and severity of
hot flushes

49. Non-hormonal Treatment
10. Clonidine and Gabapentin reduce severity and duration of hot
flushes
11. Phytoestrogens- reduce the incidence of hot flushes,
cardiovascular disease and osteoporosis
12. Thiazide diuretics reduce urinary calcium excretion

50. Hormonal Replacement Therapy(HRT)
 Benefits
o Relief of vasomotor symptoms
o Improvement in urogenital atrophy
o Reduces incidence of fractures due to osteoporosis(25-50%)
o Cardioprotective-estrogen prevents oxidation of LDL and prevents
atherosclerosis

51. HRT Associated Risks
o Endometrial cancer-risk exists with isolated estrogen replacement
therapy. progestogen supplementation recommended to prevent
endometrial proliferation under the influence of estrogen.
o Breast cancer-related to combined estrogen and progestin
replacement therapy. Dependent on dose and duration of treatment
o VTE-risk is lower with transdermal estrogen compared to oral
estrogen

52. HRT Associated Risks
o Coronary heart disease- relative risk observed with combined
estrogen and progestogen replacement
o Gallbladder disease increases with estrogen replacement,
presumably due to the increase in cholesterol and triglycerides

53. Contraindications to HRT
 Undiagnosed vaginal bleeding
 Existing estrogen dependent tumors
 History of VTE
 Active liver disease
 Gall bladder disease

54. HRT – Treatment options
 Estrogen replacement therapy-should be used alone only in women who have had a
hysterectomy to avoid endometrial hyperplasia and endometrial carcinoma
 The duration of add-on progestin therapy is critical for this effect, since 7
days/month is ineffective, whereas 13 days is protective.(last 12-14 days each
month)
 Commonly used estrogen-containing treatments include:
Oral estrogen therapy 0.3mg or 0.625mg daily
combined estrogen and progestin regime- cyclic regime with 25 days of estrogen and
progestin added on the last 12-14 days
Continuous estrogen and progestin therapy-17ꞵ estradiol subdermal implants and
transdermal patches, percutaneous estrogen gel, 1.25mg/d equine vaginal estrogen
cream.

55. Progestins
 Can be used alone where ERT is contra-indicated.
 Medroxyprogesterone acetate(MPA) 2.5-5mg/day is given.Reduces hot flushes in
90% of patients
 LNG-IUS
Protects the endometrium from hyperplasia and cancer
Releases 10mg of levonorgestrel /24 hours
2 major benefits:
i. No systemic side effects of progestins
ii. Can be employed for its contraceptive effect in peri-menopausal women
Progestins are not as effective as ERT in reducing frequency and severity of
vasomotor symptoms

56. HRT- Monitoring
 Undertaken at baseline, followed by annual follow-up testing
 Parameters include:
 Physical examination
 Blood pressure recording
 Breast examination and mammography
 TVS pelvic ultrasound to measure endometrial thickness
 Serum level of estradiol. Ideal level during HRT is 100pg/ml
 Hysteroscopy and endometrial biopsy are indicated in patients with
irregular bleeding

57. Physiology of andropause

58. Physiology of andropause
 Andropause, or late-onset hypogonadism is a syndrome occasioned
by testosterone deficiency with aging in the adult male.
 Also referred to as ADAM(Androgen decline in the adult male) or
PADAM(partial androgen decline in the adult male).
 Characterized by insidious onset and slow progression

59. Physiology of andropause
 Testosterone is the major androgen in the blood.
 The Leydig cells of the testis produce most of circulating testosterone.
Only 1% of plasma testosterone is free.
 About 11% to 59% is bound to albumin weakly and 40% to 88% is
tightly bound to sex hormone-binding globulin(SHBG)
 Bioavailable testosterone refers to albumin-bound plus free testosterone.
 Both total and free testosterone decline with aging

60. Aetiopathogenesis
 The most important reason for decreasing testicular androgen
production with aging is a decline and alteration in the number of
Leydig cells
 Age-related alterations of the hypothalamic-pituitary-gonadal axis also
contribute to a decline in testosterone production.
 Studies have shown that elderly men fail to increase their luteinizing
hormone in a response to the hypoandrogenic state, resulting in a
relative hypogonadotropic hypogonadism

61. Aetiopathogenesis
 Serum testosterone levels begin to decline at approximately 30 years of
age, with an approximate 1% decline yearly thereafter.
 In addition to the progressive decline in serum testosterone
concentrations, the sex hormone binding globulin (SHBG) level
progressively increases with age, resulting in a more pronounced
decrease in free and bioavailable testosterone compared with total
testosterone concentration

62. Aetiopathogenesis
 Other factors affecting the age-related decline in testosterone
concentration include hereditary factors, obesity, diet, stress,
depression, chronic diseases such as diabetes mellitus, coronary
atherosclerosis, chronic renal failure, chronic liver disease, sleep
apnea syndrome, and rheumatoid arthritis, and medications, such as
glucocorticoids, smoking, and alcohol intake
 The magnitude of the total testosterone decrement is on average 0.11
nmol/L (3.2 ng/dL) per year

63. Symptoms
 The symptom most associated with hypogonadism is low libido
 Other symptoms include: erectile dysfunction, decreased muscle mass
and strength, increased body fat, decreased bone mineral density and
osteoporosis, and decreased vitality and depressed mood.
 Individual symptoms are not specific for low testosterone levels but
raise clinical suspicion. Symptoms must be corroborated with a
laboratory diagnosis.

64. Diagnosis
 Criteria for diagnosis based on the EMAS prospective cohort study are as
follows:
 presence of three sexual symptoms (decreased libido, morning erections,
and erectile dysfunction)
 combined with a total testosterone level of less than 11 nmol/l and a free
testosterone level of less than 220 pmol/l,
For most symptoms, the average testosterone threshold corresponded to the
lower limit of the normal range for young men, that is, ~300 ng/dl (10.4
nmol/l) with a greater likelihood of having symptoms below this threshold
than above it

65. Consideration for Testosterone Replacement
Therapy(TRT)
1. Improving sexual function-Serum free testosterone has been found to be
significantly correlated with libido, erectile, and orgasmic function. In the presence
of a clinical picture of testosterone deficiency and borderline serum testosterone
levels, a short therapeutic trial may be justified.
2. Bone density and fracture rate-Osteoporosis is twice more common in
hypogonadal men as compared to eugonadal men (6 vs 2.8%). Bone density in
hypogonadal men of all age increases under testosterone substitution. Testosterone
produces this effect by increasing osteoblastic activity and through aromatization
into estrogen reducing osteoclastic activity.

66. Consideration for Testosterone Replacement
Therapy(TRT)
 Testosterone and Obesity, Metabolic Syndrome, and Type 2 Diabetes
Obesity, hypertension, dyslipidemia, impaired glucose regulation, and insulin
resistance) are also present in hypogonadal men.
20% to 64% of obese men have a low serum total or free testosterone levels
TRT has been shown to reduce significantly the risk of metabolic syndrome
and cardiovascular disease.

67. Consideration for Testosterone Replacement
Therapy(TRT)
 Improving anaemia- Testosterone increases renal production of
erythropoietin and directly stimulates an increase in reticulocyte
count and hemoglobin
 Cognitive performance-Lower free testosterone levels seems to be
associated with poorer outcomes on measures of cognitive function,
particularly in older men, and testosterone therapy in hypogonadal
men may have some benefit for cognitive performance.

69. TRT Contra-indications
 These include: prostate cancer, a palpable prostate nodule or
induration, prostate-specific antigen greater than 4 ng/ml or greater
than 3 ng/ml in men at high risk for prostate cancer , severe LUTs
and breast cancer
 There is no conclusive evidence that testosterone treatment increases
the risk of prostate cancer or BPH, however, there is unequivocal
evidence that testosterone can stimulate growth and aggravate
symptoms in men with locally advanced and metastatic prostate
cancer

70. References
 Benson.&.Pernoll's.Handbook.of.Obstetrics.&.Gynecology.
 DC Dutta's Textbook of Gynecology, 6th Edition
 Singh P. Andropause: Current concepts. Indian J Endocrinol Metab. 2013 Dec;17(Suppl 3):S621-9. doi:
10.4103/2230-8210.123552. PMID: 24910824; PMCID: PMC4046605
 TY - JOURAU - Reiter, SuzannePY - Barriers to effective treatment of vaginal atrophy with local
estrogen therapy, JO - International journal of general medicine
 Travison TG, Morley JE, Araujo AB, O’Donnell AB, McKinlay JB. The relationship between libido and
testosterone levels in aging men. J Clin Endocrinol Metab. 2006;91:2509–13. [PubMed] [Google Scholar]
 sidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al. Effects of testosterone on body
composition, bone metabolism and serum lipid profile in middle-aged men: A meta-analysis. Clin
Endocrinol (Oxf) 2005;63:280–93. [PubMed] [Google Scholar]
 Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: A
collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100:170–83. [PMC free
article] [PubMed] [Google Scholar]