Atlas of Clinical Andrology

Chapter 10. Andropause and osteoporosis

There is no decline in men’s fertility before the age of 35 years. However, there are normal-age related changes in the sexual response cycle in men (Tables 10.1 and 10.2). The man’s age appears to affect conception if the woman is over 35. At the age of 40 men are 40% less likely to succeed in getting their partner pregnant within a month than when they were 35. The decline in fertility is not dramatic, but men are advised to deposit a frozen semen sample at age 35 in case they want to become fathers at a later age. The superfertile period (6 days preceding ovulation) remains the same for women of all ages. It was suspected that part of the reason why it is more difficult for older women to become pregnant could have been that their fertile period was shorter than that of younger women. Assuming that couples had sexual intercourse at the best time for conception - 2 days before ovulation - and assuming that the men were the same age as the women, women younger than 27 had a 50% chance of conceiving during that menstrual cycle.

Table 10.1 Physiological events during the male reproductive cycle

Stage of life cycle


Physioanatomical events

Fetal differentiation (weeks of gestation)

5 (CRL 7)

Gonadal primordial germ cells appear

6 (CRL 16)

Seminiferous cords develop

7 (CRL 29)

Interstitial cells appear

8 (CRL 40)

Mullerian ducts regress

9 (CRL 50)

Wolffian ducts develop; urethral folds fuse into penis (first prostatic bud appears)

Adolescence (years)


Extensive development of Leydig cells


Testicular spurt and fat spurt; seminiferous tubules differentiate (spermatozoid and primary spermatocyte)


Straight pubic hair appears; Leydig cells differentiate; secondary spermatocytes appear: penis spurt and height spurt; wavy pubic hair appears


Voice deepening; first ejaculation; circumanal hair


Sperm appear; axillary hair; fat decreases; sweat and sebaceous glands are large

Reproductive senescence


Various testes size and firmness decreases; basement membrane and tunica propria of seminiferous tubules thicken; tubules decrease in diameter; degenerative changes in germinal epithelium; reduced sperm production; Sertoli cells obliterate, contain golden-brown pigment granules; progressive intertubular fibrosis causes separation of seminiferous tubules from blood supply; prostate gland enlarges, its contractions become weaker; number of coitus per year declines from 109 (35-44 years of age) to 81 (45-53 years) to 22 (65-74 years)

CRL, crown-rump length

Sexuality and fertility in men are under the control of the hypothalamo-pituitary axis. Sexuality and aging, urological factors, androgen replacement therapy and clinical parameters of andropause are related to osteoporosis and osteoporotic fractures (Comhaire, 2000; Morales et al, 2000; Olson, 2000; Schivi and Rehman, 1995; Stas et al., 2003; Vermeulen, 2001; Wespes and Schulmann, 2000). Andropause is associated with major changes in hormone profile including testosterone, melatonin and growth hormone (GH). Symptoms of andropause include excessive height loss, curvature of the spine, chronic back or spinal pain, jaw shrinkage and loss of mobility. Bone mineral density (BMD) is used to diagnose osteoporosis. There are several risk factors for osteoporotic fracture: Caucasian, low BMD, prior fracture after age 50 and hypogonadism. Secondary causes of systemic andropause include endocrine profile, malignancy, gastrointestinal disorders, drugs, genetic factors and renal failure or acidosis (Table 10.3). Decline in androgen level is associated with changes in body composition and erectile dysfunction. There are several methods of administration of testosterone therapy for older men, including injectable, transdermal, scrotal patch, non-scrotal patches with or without enhancers, testosterone gel and orals.


Bones are made of calcium and phosphorus crystals, held by protein fibers (Figures 10.1 and 10.2). Calcium produces the strength and rigidity in bones, and protein allows flexibility. Other minerals that help hold bone cells together are fluoride, sodium, potassium and magnesium. Bones are in a constant state of change and contain fluids. Bones continue to grow up to the age of 20 years, and then begin to increase in density. The bone mass of an individual depends not only on the amount of bone mass lost as a function of hormonal status and age, but also on the peak bone mass attained during growth and development (Figure 10.3). Thus, osteoporosis and attendant fractures can occur when either there is a failure to reach peak bone mass or resorption exceeds formation after peak bone mass is achieved (Eskin and Troen, 2003) (Figure 10.4). Osteoporosis results from abnormalities in bone remodeling, whereas osteomalacia results from defects in bone mineralization due to calcium deficiency.

Figure 10.1 (a) Osteocyte and bone. (b) Master cell. Co, collagen fibrils; ER, endoplasmic reticulum; M, mitochondria; X, mineralized matrix; Gr, granule; Lc, lymphocyte; N, nucleus

Osteoporosis is a skeletal disorder in which bone strength is compromised due to loss of bone density and a decline in quality of bone. Osteoporosis is due, in large part, to an uncoupling of bone formation and resorption. While current diagnostic procedures can distinguish those at risk of fracture from those not at risk, there is a large overlap in bone density between men who fracture and those who do not. There is an absolute osteoclast overactivity (possibly with increased numbers of cells) in high-turnover osteoporosis. In senile osteoporosis bone formation lags behind resorption; hence the rate of resorption is relatively higher than that of formation, resulting in a net bone loss. Osteoporosis is characterized not only by low bone mass, but also by microarchitec- tural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fractures (Eskin and Troen, 2003) (Figure 10.2).

Figure 10.2 Functional ultrastructure/biodynamics of bone formation. (a) Bone cell within the Haversian system of a membrane bone. (b) Nerve cell with axon (the long branch) and dendrites (the short branches). (c) Secretion of bone and adjacent marrow: (1) bone lamella; (2) lacunae, i.e. osteocyte space and cell; (3) osteoblast cells; (4) endosteum; (5) fat cells in bone marrow; (6) blood vessels and various other cells of bone marrow. (d) Bone adjacent to spongiosa area: (1) eroded cartilage; (2) bone cortex; (3) periosteum; (4) osteocyte embedded; (5) osteoblast; (6) bone matrix

Figure 10.3 Developmental changes of long bones

Calcium in other body functions

Calcium is deposited in bones and withdrawn as needed. Calcium has other important functions besides building strong bones and teeth. It is important in brain and nerve functions, normal blood clotting, smooth muscle contraction and expansion, acting as glue that holds cells together, transportation of chemical ions across cell membranes, and lowering blood pressure/hypertension.

In all, 99% of the body’s calcium is within bones. The average man, woman and child have sufficient calcium for their needs if they eat a balanced diet, with emphasis on the basic four food groups. Milk/milk products are the richest sources of calcium, and this type of calcium is easily absorbed by the body. Milk products, available almost everywhere, are relatively inexpensive and easy to use in almost any diet. However, not all milk products are rich in calcium. Cream cheese, coffee cream, whipped cream and butter are mostly fat, and contain little calcium. Adding more milk solids or cheese to foods prepared at home, such as puddings, custards, cream soups, bread products, pastas, casseroles and beverages, can increase the amount of calcium in the diet. Sardines and canned salmon are also good sources of calcium, especially if the tender bones are eaten.

Figure 10.4 Pathophysiology of osteoporotic fractures (Olson,2000)

Red meat and poultry are not good calcium sources. Legumes, fruits and vegetables, cereals, grains, breads and pastas are all contributors to calcium intake. When lime is added to dry corn to make hominy, or to corn meal for tortillas and other southwestern delicacies, the calcium content of corn is increased. Fruit and vegetables are also a good source of boron, a mineral that, research indicates, assists calcium absorption and bone mineralization.

Assessment of bone mineral density

BMD (area density in g/cm2) is measured using dualenergy X-ray absorptiometry, operating in fan beam mode. Quality control scans are performed daily using the manufacturer-supplied anthropomorphic spine phantom at various bone locations. The lumbar spine (LS), femoral neck (FN), Ward’s triangle (WT) and trichinae (T) are assessed. LS is assessed from L2 to L4, in the anteroposterior view. At the upper left femur, hip BMD is measured at three regions of interest: FN, WT and T. Z score expresses the BMD in relation to the average value expected for that age and is presented in age-specific SD units, while T score expresses SD units in relation to a young, healthy population. The Z and T score values are calculated using the manufacturer’s reference values, which were obtained from Greek subjects. The WHO diagnostic criteria for osteopenia and osteoporosis are used to define low bone density. According to WHO guidelines, osteoporosis is present if BMD is more than 2.5 SD below the peak bone mass reference standard for young adults (T score > -2.5 SD) (Table 10.4).

Table 10.4 Diagnosis of osteoporosis based on bone mineral density


Bone mineral density (T score)


≤- 1 SD


-1 to -2.5 SD


≥-2.5 SD with history of fragility fracture


With increasing life expectancy and decreasing reproduction rate, the population structure is changing. Extensive investigations have been conducted on the biology of andropause in men (Tables 10.5-10.7). In aging men the typical patterns of daily rhythmicity become less distinct. This is part of a very complex picture in which not only isolated hormones are involved, but also interactions between hormones. Many factors from the external and internal environment mediated by neurotransmitters constantly affect the highly sensitive hormonal balance. Therefore, aging has also been defined as ‘the gradual dysfunction of homeostatic processes’.

Declining testosterone levels are involved in ‘andropausal’ symptoms in men: loss of libido, erectile dysfunction, insulin receptor resistance, obesity, osteoporosis, disturbances of lipid metabolism, myocardial and circulatory disturbances, and impaired well-being and mood. Data have been derived from studies in hypogonadal men treated by testosterone replacement. In such patients libido increases, fat mass decreases, and muscle strength, BMD and erythropoiesis increase. Atherosclerotic plaque size is reduced after estrogen injections in cholesterol-fed rabbits. Phytoestrogen-fed monkeys had lower total cholesterol and low-density lipoprotein (LDL) cholesterol and higher high-density lipoprotein (HDL) cholesterol. Apart from atherosclerotic lesions, coronary artery vascular reactivity is improved.

Testosterone supplements

The delivery systems of testosterone supplements include: DPT (Depo®-testosterone, 400 mg intramuscularly every 2-3 weeks), TSD (Testoderm® scrotal patches, 4-6 mg/24 h and TTS (Testoderm® non-scrotal patches, 5 mg/24 h) (Table 10.8).


Osteoporosis is one of the commonest metabolic bone diseases, and its prevalence is expected to rise as the population grows older. Although osteoporosis is less prevalent in men than in women, the morbidity and mortality associated with male osteoporosis is greater. Severe osteoporosis in non-elderly men is usually associated with conditions involving bone loss, such as hypogonadism, hypercorticolism, hyperthyroidism and excessive alcohol intake (Table 10.6). If no known cause of bone disease can be identified it is termed idiopathic. Idiopathic osteoporosis (IO) is more commonly encountered in men than in women. The lack of identifiable causes of reduced bone density in men with IO has led to the suggestion that this disorder is the result of major abnormalities in bonecell function or of the hormonal or paracrine pathways that regulate bone-cell metabolism. Growth hormone (GH), insulin- like growth factor I (IGF-I) and its major binding protein insulin-like growth factor binding protein-3 (IGFBP-3) could be major causes.

Table 10.8 Testosterone replacement for older men


Dose and frequency of administration


Testosterone-enanthate/ cypionate

100-200 mg every 2 weeks



Scrotal patch

6 mg/day

Non-scrotal patches with enhancers

5 mg/day

Non-scrotal patches without enhancers

5 mg/day

Testosterone gel

5-10 mg/day (5-10 g of gel)


Testosterone undecanoate (not available in USA)

80 mg bid or tid

Symptoms, diagnosis and risk factors of osteoporosis

Symptoms of osteoporosis include:

(1) Excessive height loss (loss of > 6 inches in height);

(2) Curvature of the spine - sign of vertebrae collapsing, distinctive hump below shoulders in severe cases;

(3) Chronic back or spinal pain, due to bone degeneration;

(4) Jaw shrinkage - demineralization of jaw bone and teeth, dentures become less secure and need to be replaced;

(5) Loss of mobility - decreased flexibility, becoming severe and appearing earlier when the effects of osteoporosis, restricted body movement, leads to insecurity.

Table 10.9 Pharmacotherapy in older men: comparison of selected medications




Tricyclic antidepressants





Inexpensive, once daily dosing

Anticholinergic side-effects, multiple Drug interactions



Selective serotonin reuptake inhibitors Sertraline




Safer in overdosage, once daily dosing

Sexual dysfunction, nausea



Cytochrome P450 interactions

Serotonin antagonist reuptake inhibitors Trazodone


Few drug interactions, once daily dosing

Sexual dysfunction, priapism

Possible cardiotoxicity

Serotonin-norepinephrine reuptake inhibitors Venlafaxine

Favorable side-effect profile

Hypertension, sexual dysfunction

Hyperlipidemia, multiple daily dosing


Appetite stimulant

Sexual dysfunction, blood dyscrasias, dependence potential

Dopamine reuptake inhibitors


Safer in overdose, minimal cardiotoxicity


Alternative therapy

Favorable side-effect profile

Lack of regulatory standardization, insufficient objective data

St John’s wort

Treatment and therapy

Regular daily exercise should become a lifetime habit. Persons not already involved in regular exercise programs should consult a doctor before starting.

Consuming 1500 mg of calcium in the diet every day protects most menopausal women. Younger women should take 1000 mg of calcium daily. Greater amounts of calcium should be taken only under direction of a doctor. Those who cannot digest milk may tolerate yogurt or buttermilk because both already contain lactase. Lactase, in the form of Lact-AID, is available at drugstores, and can be added to milk products to aid digestion. Calcitonin, a thyroid gland hormone, is prescribed to slow bone breakdown. Estrogen helps calcium retention and maintains healthy bones, and is sometimes prescribed for postmenopausal women. Any hormone therapy should be considered carefully, prescribed and periodically monitored by a doctor.

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