12.6 — The Gonads as Endocrine Organs

The ovaries and testes do two jobs at once: they make gametes, and they make hormones. Part 15 covers the reproductive anatomy in full. This chapter covers only the endocrine half — the hormones themselves, what they do outside reproduction, and what happens when they are too high or too low.

And the "outside reproduction" part is larger than most people expect. Sex hormones affect bone density, muscle mass, fat distribution, cholesterol, blood vessels, mood, cognition, skin and hair. They are not reproductive hormones that happen to have side effects; they are systemic hormones with a reproductive role.

The shared control axis

Both sexes use the same three-level arrangement (Chapter 12.1).

Hypothalamus → GnRH → pituitary → LH and FSH → gonad → sex steroids → negative feedback.

GnRH must be pulsatile. Roughly every 60 to 90 minutes. Continuous GnRH shuts the axis down, which is the therapeutic paradox from Chapter 12.1: GnRH agonists are used to suppress sex hormones in prostate cancer, endometriosis, fibroids and precocious puberty.

In males: LH acts on the Leydig cells to make testosterone. FSH acts on the Sertoli cells to support sperm production.

In females: LH and FSH together drive follicle development and ovulation, and control oestrogen and progesterone production across the cycle (Chapter 15.4).

And the female axis contains the body's only physiological positive feedback loop — the LH surge that triggers ovulation.

Testosterone

Made mainly in the testes, with a small contribution from the adrenal cortex. Women produce testosterone too, at about a tenth to a twentieth of male levels, and it matters to them.

In many target tissues, testosterone is converted to a more potent form — dihydrotestosterone — by the enzyme 5-alpha-reductase.

And blocking that enzyme is the basis of two common drugs. Finasteride shrinks the prostate (Chapter 10.5) and slows male pattern hair loss, because both are driven by dihydrotestosterone rather than by testosterone itself.

Testosterone is also converted to oestrogen by the enzyme aromatase, in fat tissue and elsewhere. Which means men make oestrogen, from their own testosterone, and need it — men lacking aromatase or the oestrogen receptor have poor bone density and growth plates that never close (Chapter 5.1).

What testosterone does:

Before birth — drives development of male internal and external anatomy (Chapter 4.5).

At puberty — genital growth, deepening voice, facial and body hair, muscle growth, the growth spurt and then growth plate closure, and increased sebum production, which is why acne is a puberty disease.

Throughout life — maintains muscle mass and strength, bone density, red cell production, libido, and sperm production. It also affects mood, energy and cognition, though those effects are more variable and harder to measure.

Levels decline gradually with age — roughly 1 percent a year after about 30 to 40.

And this brings up a topic that needs stating carefully, because it is heavily commercialised.

"Male menopause" is a misleading term. Women's hormone production ceases over a defined period; men's declines gradually and never stops, and many men in their eighties have levels within the young adult range.

Genuine late-onset hypogonadism exists — low testosterone with symptoms — and it is worth diagnosing, because replacement genuinely helps those men.

The diagnosis requires both symptoms and consistently low measured levels, on morning samples taken twice, because testosterone follows a daily rhythm and a single afternoon sample is uninterpretable.

And a great deal of what is diagnosed as low testosterone is something else. Obesity, sleep apnoea, depression, excess alcohol, opioid use and chronic illness all lower testosterone, and treating those raises it without any hormone at all. Obesity is particularly important: fat tissue converts testosterone to oestrogen, and weight loss raises testosterone measurably.

Testosterone replacement in men with genuinely low levels improves libido, mood, muscle mass and bone density. Testosterone given to men with normal levels for vague symptoms of ageing has weak evidence of benefit and real risks, and the distinction is routinely blurred by clinics selling it.

Its risks: raised red cell count with a thrombosis risk, worsening of sleep apnoea, prostate stimulation — it does not appear to cause prostate cancer but can accelerate an existing one — and, importantly, suppression of the axis, which shrinks the testes and stops sperm production.

That last point catches men out. Taking testosterone is an effective male contraceptive, and men taking it for fertility problems are making them worse. A man wanting both testosterone and fertility needs a different approach entirely.

Anabolic steroid misuse deserves an honest paragraph, because the doses used are 10 to 100 times replacement levels and the consequences are substantial: testicular shrinkage and infertility, breast development from aromatisation, acne, hair loss, aggression and mood disturbance, raised cholesterol, high blood pressure, thickened heart muscle, and liver damage from oral forms. Some effects reverse on stopping; testicular suppression can take a year or more to recover and occasionally does not.

Oestrogen and progesterone

Oestrogen — mainly oestradiol in the reproductive years, made by the ovarian follicles.

And after menopause it is not zero. Fat tissue converts adrenal androgens to a weaker oestrogen, oestrone, which is why heavier postmenopausal women have higher oestrogen levels and, correspondingly, a higher risk of endometrial and breast cancer and a lower risk of osteoporosis.

What oestrogen does:

At puberty — breast development, widening of the pelvis, fat redistribution, the growth spurt and growth plate closure.

In the cycle — thickens the endometrium, thins the cervical mucus (Chapter 4.3).

Throughout life, and this is the underappreciated part:

Bone. Oestrogen restrains osteoclasts. Its withdrawal at menopause causes accelerated bone loss of 2 to 3 percent a year for several years (Chapter 5.9). This single effect explains why osteoporosis is so much commoner in women.

Cardiovascular. Oestrogen improves the cholesterol profile and helps maintain blood vessel function. Premenopausal women have substantially lower cardiovascular risk than men of the same age, and the gap narrows after menopause.

Skin — maintains collagen. Skin collagen falls by about 30 percent in the first five years after menopause, which accounts for a large part of the visible change.

Brain, urogenital tissue, and cognition — with effects that are real and harder to quantify.

Progesterone — made by the corpus luteum after ovulation, and by the placenta in pregnancy.

Its name is a description: pro-gestation. It prepares the endometrium for implantation, maintains pregnancy, thickens cervical mucus to a barrier, and slightly raises body temperature — about 0.3 to 0.5 °C after ovulation, which is the basis of temperature-based fertility tracking.

It also relaxes smooth muscle, which explains several features of pregnancy at once: constipation, reflux, and increased urinary frequency (Chapter 15.6).

Puberty

Driven by the reawakening of pulsatile GnRH, which is active in infancy, goes quiet through childhood, and restarts at puberty.

Why it restarts is not fully understood. A protein called kisspeptin and its receptor are essential — people lacking either do not enter puberty — and body fat, through leptin, contributes to the timing. The full trigger remains an open question, which is worth saying rather than glossing over.

In girls: breast development first (around 8 to 13), then pubic hair, then the growth spurt, then the first period (typically 12 to 13, about 2 to 2.5 years after breast development begins).

In boys: testicular enlargement first (around 9 to 14), then penile growth and pubic hair, then the growth spurt — which comes later than in girls, at around 13 to 15.

Which is why girls are on average taller than boys for a couple of years in early adolescence, and why boys end up taller: they grow for longer before their plates close, and their spurt is larger.

Precocious puberty — before 8 in girls or 9 in boys. Usually no cause is found in girls; in boys it is much more often due to an underlying problem and is investigated more aggressively.

And there is a real cost to leaving it untreated. Early sex hormone exposure closes the growth plates early, so a child who is initially tall for their age ends up shorter as an adult. Treatment is a GnRH agonist, using the continuous-exposure paradox to switch the axis off until an appropriate age.

Delayed puberty — no signs by 13 in girls or 14 in boys. Usually constitutional delay — a normal variant, often with a family history — and it resolves. But it can indicate chronic illness, malnutrition, excessive exercise, or a genuine hormonal problem.

Menopause

The permanent end of ovulation, defined retrospectively after 12 months without a period. Average age around 51.

The mechanism is the exhaustion of the follicle pool. A female fetus has about 6 to 7 million eggs at 20 weeks, about 1 to 2 million at birth, about 300,000 at puberty, and around 1,000 at menopause. Only about 400 are ever ovulated; the rest are lost by attrition throughout life (Chapter 15.4).

So menopause is not the ovaries switching off — it is running out of the material they work on.

Perimenopause — the transition, typically 4 to 8 years, with fluctuating and often erratically high hormone levels. The fluctuation is what causes the symptoms, more than the low level.

Symptoms: hot flushes and night sweats in around 75 percent, sleep disturbance, mood changes, brain fog, joint aches, and vaginal dryness and urinary symptoms, which unlike the others do not resolve with time and tend to worsen.

Hot flushes deserve an explanation because the mechanism is now reasonably understood. Oestrogen withdrawal narrows the hypothalamic thermoregulatory set point range (Chapter 4.7), so a small rise in core temperature that would normally be ignored triggers a full heat-loss response — flushing and sweating. New non-hormonal drugs targeting the specific neurons involved have recently been approved, which is a direct result of working out the mechanism.

Hormone replacement therapy needs a careful and honest paragraph, because the messaging has swung badly in both directions.

In 2002 the Women's Health Initiative trial reported increased breast cancer and cardiovascular risk, and HRT use collapsed worldwide.

Subsequent reanalysis found the picture was substantially more nuanced. The trial population was older than typical HRT users — average age 63, many more than a decade past menopause — and the risks differed markedly by age and by preparation.

The current position, stated as it stands:

For most women under 60, or within 10 years of menopause, with troublesome symptoms, the benefits of HRT outweigh the risks.

It is the most effective treatment for hot flushes, and it prevents osteoporosis.

Oestrogen alone, in women who have had a hysterectomy, carries little or no increased breast cancer risk in the trial data. Combined oestrogen and progestogen carries a small increased risk — of the order of a few extra cases per thousand women per year — and progestogen is necessary in women with a uterus, because unopposed oestrogen causes endometrial cancer.

Transdermal oestrogen — patches or gel — avoids the increased clot risk seen with oral preparations, because it bypasses the liver's first pass (Chapter 7.5).

Vaginal oestrogen for local symptoms is very low dose, barely absorbed, and safe for essentially everyone, including most women who cannot take systemic HRT. It is substantially underused, and it treats a set of symptoms that women are frequently too embarrassed to raise.

Starting HRT for the first time over 60, or more than 10 years after menopause, has a less favourable balance.

And the honest summary is that this is a decision to be made individually, with accurate figures, rather than by a blanket rule in either direction. The swing from over-prescription to near-abandonment and back has left a generation of women poorly served by both.

Premature ovarian insufficiency — menopause before 40 — affects about 1 percent of women, and here HRT is not optional but recommended until at least the natural age of menopause, because decades of oestrogen deficiency carry substantial bone and cardiovascular consequences.

Polycystic ovary syndrome

The commonest endocrine disorder in women of reproductive age — around 8 to 13 percent.

Diagnosed when two of three features are present: irregular or absent ovulation, clinical or biochemical excess androgens, and polycystic-appearing ovaries on ultrasound.

And the name is unhelpful, because the "cysts" are not cysts — they are ordinary follicles arrested part-way through development. Many women with the syndrome have normal-appearing ovaries, and many women with polycystic-appearing ovaries do not have the syndrome.

The mechanism links insulin and androgens. Insulin resistance is central, present in a majority regardless of weight. High insulin stimulates the ovary to produce androgens and lowers the protein that binds sex hormones in blood, raising free testosterone further.

The consequences: irregular periods, difficulty conceiving, acne and hirsutism, and substantially increased long-term risk of type 2 diabetes, gestational diabetes and cardiovascular disease — which is the part that is most often left out of the conversation and matters most over a lifetime.

Treatment follows the goals rather than the label.

For irregular periods and long-term protection: the combined contraceptive pill, or cyclical progestogen. This matters more than it sounds — infrequent periods mean the endometrium is exposed to oestrogen without progesterone, which raises endometrial cancer risk.

For fertility: letrozole is now first-line, ahead of clomifene.

For insulin resistance: metformin, and weight loss where relevant. A 5 to 10 percent weight loss frequently restores ovulation, which is a large effect from a modest change.

For hirsutism: hormonal treatment plus cosmetic measures, and expectations set honestly — it takes six months to see a difference, because that is the hair growth cycle (Chapter 14.3).

What the next page fixes

Three small glands remain, one of which was thought useless for most of medical history. Chapter 12.6 completes the endocrine system with the pineal gland and the body clock, the thymus, and the hormones produced by organs nobody thinks of as endocrine at all.