Stuart R. Gallant, MD, PhD

Steroid hormones are frequently in the news—sometimes in infamy, as in the case of sports doping, but also in many medical uses (for example, hormone blocking therapies for cancer and hormone replacement therapies for hormone deficiency).  In the first part of this two-part post, we will look at the pharmacology of androgens (male hormones) and estrogens (female hormones).  In the second part, we will look at steroid hormone replacement therapy.

Distributed Endocrine Signaling

The endocrine system is a complex, interconnected system of signaling and control which uses molecules like steroid and peptide hormones to coordinate activity, development, behavior, and reproduction throughout the body.  For the steroid hormones three tissues are particularly important:

• Pituitary:  The pituitary gland receives signals from the hypothalamus and releases signaling hormones (such as luteinizing hormone (LH) and follicle stimulating hormone (FSH)) into the blood.
• Adrenal Glands:  The two adrenal glands produce aldosterone (which controls salt and therefore blood pressure) and cortisol (which controls stress response), as well as some androgens and estrogens.
• Ovaries (women) and Testes (men):  The lion’s share of androgens in men and estrogens in women are produced in the testes (men) and ovaries (women).

To circulate throughout the body, steroids hitch a ride on proteins present in blood (chiefly, albumin, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG)) [1].  This mechanism increases the carrying capacity of blood for steroid hormones, like a fleet of buses increases the ability of commuters to move around a city.  As testosterone and estrogen circulate through the body, they may be imported into different tissues and bind to cellular receptors changing the behavior of the cells (for example to increase muscle mass or fat distribution of the body).

Steroid Hormone Structure and Synthesis

In the figure below, the structures of cholesterol and the steroid hormones testosterone and estradiol are shown side-by-side:

All three molecules share the same skeleton of 4 rings.  Only small structural changes in the lefthand ring account for the difference in effect of testosterone versus estradiol.

The reason for the similarity of cholesterol’s structure to that of the steroid hormones is that cholesterol is the starting material for steroid hormone synthesis.  Enzymes present in the adrenal glands, testes, and ovaries make sequential chemical changes to cholesterol in order to produce a tool kit of steroid hormones which have a range of roles within the body.  The classic steroid synthesis diagram well known by every medical student is:

To understand this diagram, start at the upper left:

• Synthesis of all steroid hormones starts with cholesterol which is the starting material for steroid hormones.  Individual biochemical reactions catalyzed by enzymes create intermediate products, leading to the final products (aldosterone which controls salt in the body, cortisol which controls stress response, and the androgens (dehydroepiandrosterone (DHEA), androstenedione, testosterone, dihydrotestosterone, and related molecules not shown) and estrogens (estrone, estradiol, and estriol (produced from estrone and estradiol in the liver and placenta)).
• The balance of steroid hormone production is divided between the adrenal glands, the ovaries and testes.  In men, the major locus of androgen production is in the testes. In women, the major locus of estrogen production is in ovaries.
• In adipose (fat) tissue, testosterone and androstenedione are converted to estrogen.  One reason for a modest increase in the rates of cancer with obesity is that estrogen dependent cancers are supported by this increased estrogen.

Testosterone Levels in Men (and Women)

Testosterone’s most prominent roles include:  differentiating boys from girls during fetal development, causing development of male secondary sexual characteristics during puberty, promotion of spermatogenesis in males, increased libido, and anabolic effects (increased muscle and bone mass, as well as increased red blood cell count).

Adult men produce 6-7 mg of testosterone per day of which 95% is produced by the testes [2].  As depicted in the schematic diagram below, secretion is controlled by both signaling in the forward direction and feedback control:

Key features include:

• Hypothalamus and Pituitary Gland of the Brain:  The hypothalamus signals with GnRH, and the pituitary responds by releasing luteinizing hormone (LH) and follicle stimulating hormone (FSH).
• Leydig Cells in the Testes:  Upon stimulation by LH, the Leydig cells of the testes release testosterone and DHT which bind receptors in various parts of the body, changing protein expression.
• Negative Feedback:  As testosterone level increases in the blood, it has a negative effect on the hypothalamus and pituitary—reducing LH release.  This prevents limits testosterone production.  Thus, testosterone levels in adult men are controlled in the range of 300 to 1000 nanograms per deciliter.
• Diurnal Cycle:  There is a modest variation of testosterone during the course of the day [3].  A plot of average values obtained from young (average 25 yr) and old (average 71 yr).  Of note, there is a modest rise in testosterone which peaks about 8 am.  Because of this daily variation, laboratory test samples for testosterone are typically drawn in the morning prior to breakfast (i.e., fasting):

Women also produce testosterone but at lower levels of 15-70 ng/dL.  Women’s production of androgens is divided between the ovaries and adrenal glands and varies by the time within the woman’s cycle [4]:

Hormone	Adrenal Contribution	Ovarian Contribution (Folicular/Midcycle/Luteal)
Testosterone	40-60%	33%/60%/33%
DHT	50%	50%
Androstenedione	30-55%	45%/70%/60%
DHEA	80%	20%
DHEA-S	90-96%	4%/10%/4%

Estrogen and Progesterone Levels in Women

Estrogen and progesterone’s most prominent roles include: 

The intricate choreography of the women’s monthly cycle is shown in the schematic diagram below:

Key features of the cycle include:

• Follicle stimulating hormone (FSH) promotes production of eggs within the ovaries.
• Estradiol production by the ovaries increases, stimulating thickening of the uterine lining.  Estradiol varies between less than 50 pg/mL at Day 1 to around 250 pg/mL at Day 14.
• If fertilization does not occur, falling levels of progesterone trigger shedding of the lining, and the cycle repeats.  Progesterone varies between less than 1 ng/mL at Day 1 to around 14 ng/mL at Day 14.

As women age, changes in the cycle occur:

• In perimenopause, the levels of FSH and estradiol can vary dramatically and irregularly.
• In menopause, estradiol and progesterone production by the ovaries decreases markedly.

In the second part of this two-part post, we will look at hormone replacement therapy.

[1] Hammond, G. L.  “Plasma steroid-binding proteins:  primary gatekeepers of steroid hormone action,” Journal of Endocrinology, 230, R13–R25 (2016).

[2] Behre, H.M.  “Male Reproductive Function,” International Encyclopedia of Public Health, 2nd edition, Volume 4, 529-536 (2017).

[3] Bremner, W.J., et al.  “Loss of Circadian Rhythmicity in Blood Testosterone Levels with Aging in Normal Men,” Journal of Clinical Endocrinology and Metabolism, 56, 1278-1281 (1983)

[4] Abraham, G.E., et al.  “Ovarian and Adrenal Contribution to Peripheral Androgens During the Menstrual Cycle,” JCE & M, 39, 340-346 (1974).

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