How androgens work in the female body

Female endocrine glands secrete five different androgens, all via a similar pathway:

1. Testosterone and its biologically active form, dihydrotestosterone (DHT) (both with direct androgenic activity)
2. Dehydroepiandrosterone sulfate (DHEAS) (precursor to testosterone)
3. Dehydroepiandrosterone (DHEA) (precursor to testosterone)
4. Androstenedione (precursor to testosterone)
5. Androstenediol (has both oestrogenic and androgenic activity) (precursor to testosterone)

The ovary and production of testosterone

The ovaries produce about a quarter of all circulating testosterone, which requires the production of luteinising hormone (LH), which is a hormone secreted by the anterior pituitary. The ovaries secrete around half of the androstenedione and 20 per cent of the DHEA.

Testosterone testing in women can be used to check ovarian androgen secretion, but the adrenal glands also contribute to testosterone. The adrenals convert androstenedione to testosterone.

The adrenal glands and production of testosterone

The adrenals produce all the DHEAS and 80 per cent of the DHEA in the body, with half of the androstenedione and a quarter of circulating testosterone. DHEAS and 11-androstenedione are not provided by the ovaries, and thus are used as a marker of adrenal androgen production and secretion.

The adrenal glands rely on adrenocorticotropic hormone (ACTH), which is secreted by the anterior pituitary gland in the brain. Prolactin and oestrogen can impact adrenal androgen production.

How the skin, fat, liver and urogenital system produce androgens

There are other systems that are key sites of androgen production, which includes the skin – androstenedione, and some DHEA, are converted to testosterone in the skin. Fat cells contribute about half of circulating testosterone, where androstenedione is converted to testosterone.

How androgens impact our body systems

Only testosterone and DHT are able to activate androgen receptors throughout the body. In healthy women, 80 per cent of testosterone is bound to sex hormone binding globulin (SHBG), 19 per cent is bound to albumin, and one per cent is freely circulating in the blood. If the unbound fraction is high, androgenicity is higher, with the levels of SHBG dependent on many factors, including diet and medications.

How to increase SHBG levels to decrease circulating testosterone

• Increase in oestrogens
• Thyroid hormones
• Pregnancy
• Oestrogen-containing medications or preparations
• Certain foods

How to decrease SHBG levels to increase circulating testosterone

• Increase androgens
• Increase in synthetic progestins – for example those found in the oral contraceptive pill (norethindrone, norgestrel, desogestrel, norgestimate)
• Glucocorticoids
• Growth hormone
• Insulin
• Obesity (which tends to increase insulin)
• Acromegaly
• Hypothyroidism
• Hyperinsulinemia

DHEAS, DHEA and androstenedione are almost completely bound to albumin, which has a low affinity for sex hormones. Albumin-bound androgens are much more bioavailable to tissue.

Things to know about androgens in the body

• Adrenal androgens rise when stimulated by ACTH
• Androgens do not increase or decrease ACTH secretion
• LH stimulates theca cells of the ovaries to secrete androgens
• No feedback loop exists to control androgen secretion in women
• Most circulating testosterone is metabolised in the liver, resulting in androsterone and etiocholanolone, which are then excreted in the urine (after conjugation)
• Up to 30 per cent of urinary 17-ketosteroids are from testosterone metabolism, with the rest from metabolism of adrenal steroids

The role of androgens in a growing foetus

Androgens cause a male foetus to develop external and some internal male reproductive tissue – penis, testicles, seminal vesicles, prostate. If these androgens do not kick in – or their effect is interrupted somehow (presence of a 46 XY karyotype found in androgen insensitivity syndrome) – then a female phenotype (female-looking) body will develop, since female is the default.

In females outside of the womb, androgens in excess will induce sexual hair growth, balding, acne, clitoral growth, sebum production, and a deeper voice.

The effects of androgens throughout the body

Androgens have direct and indirect impacts on tissue throughout the body, with many of these effects being mysterious to the scientific medical community. We have androgen receptors in muscle, skin, our intestines, the genitourinary tract, bones, brain, blood vessels and cardiovascular system, placenta, and fat tissue.

The effect of androgens on the brain

Androgens impact the brain due to androgen receptors being found throughout brain tissue, very close to estrogen receptors. The most androgen receptors are located near to the hypothalamus, with some areas of the brain able to convert testosterone to DHT or oestradiol. Androgens may have an activational behaviour on women, with some negative side effects observed on the cognitive functions of older women.

Androgens are thought to be involved in sexual desire, with decreased sexual function reported in women with very low androgen levels due to antiandrogen medication. Administration of testosterone to women with hypoactive sexual desire disorder regulates sexual function and libido, improving the condition.

The effect of androgens on bones

Androgens impact bones via mineralisation due to the direct or indirect aromatisation of androgens to oestrogen. Low androgen concentrations are associated with bone loss in some age groups.

The effect of androgens on breasts

Androgen receptors exist on breast cells, along with oestrogen and progesterone receptors. Androgens may play a role in protecting breast tissue, but human studies are lacking. Women with excess androgens associated with polycystic ovarian syndrome (PCOS) don’t appear to have extra risk of breast cancer.

One study showed no significant difference in postmenopausal women when testosterone was added to oestrogen and progesterone, but a five-fold increase in breast cell proliferation in women taking the placebo.

The effect of androgens on the endometrium

Androgens may have an inhibitory effect on endometrial proliferation.

The effect of androgens on the cardiovascular system

Women with PCOS are at a higher risk of cardiovascular events, but insulin resistance in relation to this condition may have more to do with this than androgens. Trans gender people transitioning from female to male have not seen an increase in cardiovascular events.

How androgens work in cells

Androgens enter the cell via diffusion across the cell membrane, and once inside the cell, bind to and activate the androgen receptors.

The androgen-receptor complex is then attached to a DNA site, stimulating messenger RNA, which then stimulates enzyme and protein production to exert the androgenic effect.