Oestrogen and progesterone are the primary female sex hormones. They are controlled by the hypothalamic-pituitary-gonadal axis and fluctuate during the menstrual cycle. This section covers:
- Oestrogen and progesterone
- Hypothalamic-pituitary-gonadal axis
- Female puberty
- The menstrual cycle
- Polycystic ovarian syndrome
- Hormonal contraception
- Menopause
- Hormone-replacement therapy
- Medications relating to oestrogen and progesterone
Oestrogen
Oestrogen is a steroid sex hormone mainly produced by the granulosa cells of the follicles in the ovaries in women. The most prevalent and active version of oestrogen is 17-beta oestradiol.
Oestrogen is also produced in smaller amounts by the:
- Adrenal glands
- Adipose (fat) tissue (converting androgens to oestrogen with the help of aromatase)
- Testes in males (converting androgens to oestrogen with the help of aromatase)
CLINICAL RELEVANCE
Aromatase is an important enzyme found in adipose tissue that converts androgens (e.g., testosterone) into oestrogen. Adipose tissue is the primary source of oestrogen in postmenopausal women (when the ovaries have stopped producing oestrogen). Aromatase inhibitors (e.g., letrozole and anastrozole) work by blocking the action of aromatase, reducing how much oestrogen is produced. They are used to lower the oestrogen level in postmenopausal women with breast cancer that is sensitive to oestrogen.
Oestrogen stimulates oestrogen receptors to have many effects on the tissues. It promotes:
- Breast tissue development
- Thickening of the endometrium
- Healthy vagina and vulva (maintaining strength, elasticity and lubrication)
- Skin thickness, elasticity and healing
- Bone density
- Cognition, mood, sleep and energy
- Immune function
Progesterone
Progesterone is a steroid sex hormone produced by the corpus luteum after ovulation. The corpus luteum is the temporary collection of cells that are leftover from the follicle after the ovum has been released. When pregnancy occurs, progesterone is produced mainly by the placenta from 10 weeks gestation onwards.
Progesterone stimulates progesterone receptors. Oestrogen increases the number of progesterone receptors. Therefore, progesterone acts on tissues that have previously been “primed” by oestrogen. Progesterone acts to:
- Thicken and maintain the endometrium (preparing the endometrium before and maintaining it during pregnancy)
- Thicken the cervical mucus
- Promote glandular tissue growth in the breasts
- Increase the body temperature
The terms around progesterone can be confusing. There are some key definitions to remember:
- Progestogens refer to any chemicals that target and stimulate progesterone receptors
- Progesterone is the hormone produced naturally in the body
- Progestins are synthetic progestogens
Hypothalamic-Pituitary-Gonadal Axis
The hypothalamus releases gonadotropin-releasing hormone (GnRH). GnRH stimulates the anterior pituitary to produce luteinising hormone (LH) and follicle-stimulating hormone (FSH).
LH and FSH stimulate the development of follicles in the ovaries. FSH stimulates the growth and development of the follicle and the granulosa cells. LH stimulates the theca cells (around the outside of the follicle) to produce androgens (e.g., testosterone). These androgens diffuse into the granulosa cells in the follicles. FSH stimulates the granulosa cells to produce aromatase, an enzyme that converts androgens to oestrogen.
Oestrogen travels to the body tissues to carry out its effects. It also travels to the brain and influences the release of GnRH, FSH, and LH from the hypothalamus and anterior pituitary. It mostly has a suppressing effect (providing negative feedback), reducing the release of GnRH, FSH, and LH. However, oestrogen has a stimulating effect (providing positive feedback) just before ovulation, causing the surge in LH that triggers ovulation.
Inhibin is a hormone secreted by the granulosa cells of the ovaries that provides additional negative feedback to the pituitary. FSH stimulates the secretion of inhibin, and inhibin has a suppressing effect on the anterior pituitary, reducing the secretion of FSH.
Female Puberty
In childhood, girls have relatively little GnRH, LH, FSH, oestrogen, and progesterone in their system. During puberty, these hormones start to increase. The hypothalamus starts to secrete GnRH, initially during sleep and then throughout the day in the later stages of puberty. GnRH stimulates the release of FSH and LH from the pituitary gland. FSH and LH stimulate the ovaries to produce oestrogen and progesterone.
In girls, puberty starts with the development of breast buds, followed by pubic hair and finally, the onset of menstrual periods. The first episode of menstruation is called menarche. Menstrual periods usually begin about two years after puberty starts. Puberty starts at age 8 – 14 in girls and 9 – 15 in boys. It takes about four years from start to finish. Girls have their pubertal growth spurt earlier in puberty than boys.
Overweight or obese girls tend to enter puberty at an earlier age. Aromatase (an enzyme found in adipose tissue) converts androgens to oestrogen. More adipose tissue means more aromatase and more oestrogen creation. Delayed puberty can occur in girls who are underweight (e.g., chronic disease, eating disorders or athletes).
Menstrual Cycle
The menstrual cycle consists of two phases: the follicular phase and the luteal phase. The follicular phase is from the start of menstruation to the moment of ovulation (the first 14 days in a 28-day cycle). The luteal phase is from the moment of ovulation to the start of menstruation (the final 14 days of the cycle).
The Follicular Phase
From puberty, the ovaries have a finite number of cells that have the potential to develop into eggs. These cells are called oocytes. Granulosa cells surround the oocytes, forming structures called follicles.
Follicles go through four key stages of development in the ovaries:
- Primordial follicles
- Primary follicles
- Secondary follicles
- Antral follicles (also known as Graafian follicles)
Primordial follicles are constantly maturing into primary and secondary follicles, independent of the menstrual cycle. Once the follicles reach the secondary follicle stage, they have the receptors for follicle-stimulating hormone (FSH). Further development after the secondary follicle stage requires stimulation from FSH.
The menstrual cycle starts (day 1) on the first day of bleeding (the first day of the period). At the start of the menstrual cycle, FSH stimulates further development of the secondary follicles. As the follicles grow, the granulosa cells that surround them secrete increasing amounts of oestradiol (oestrogen). The rising oestrogen causes the cervical mucus to become more permeable, allowing sperm to penetrate the cervix around the time of ovulation.
One of the follicles becomes the dominant follicle. Luteinising hormone (LH) spikes just before ovulation, causing the dominant follicle to release the ovum (an unfertilised egg) from the ovary. Ovulation happens 14 days before the end of the menstrual cycle, for example, day 14 of a 28-day cycle or day 16 of a 30-day cycle.
The Luteal Phase
After ovulation, the follicle that released the ovum collapses and becomes the corpus luteum. The corpus luteum secretes high levels of progesterone. Progesterone maintains the endometrium and thickens the mucus in the cervix so that it is no longer penetrable. The corpus luteum also secretes a small amount of oestrogen.
When fertilisation occurs, the syncytiotrophoblast of the embryo secretes human chorionic gonadotropin (HCG). HCG maintains the corpus luteum. Without hCG, the corpus luteum degenerates.
CLINICAL RELEVANCE
Pregnancy tests (urine or blood) check for human chorionic gonadotropin (HCG) released by the embryo.
When the ovum is not fertilised, no hCG is produced, and the corpus luteum degenerates, stopping the production of oestrogen and progesterone. The fall in oestrogen and progesterone causes the endometrium to break down and menstruation to occur. Withdrawal of progesterone causes the stromal cells of the endometrium to release prostaglandins. Prostaglandins stimulate the breakdown of the endometrium and uterine contractions, ejecting blood and endometrial tissue. Menstruation (bleeding) typically lasts 2-8 days.
Menstruation starts on day 1 of the menstrual cycle, marking the start of the next follicular phase. A lack of negative feedback from oestrogen on the hypothalamus and pituitary gland allows the levels of LH and FSH to begin to rise and the cycle to restart.
Female Hypogonadism
Hypogonadism refers to a lack of sex hormones, specifically oestrogen in females. It can be categorised into:
- Primary hypogonadism, caused by a problem with the ovaries
- Secondary hypogonadism, caused by a problem with the pituitary
- Tertiary hypogonadism, caused by a problem with the hypothalamus
Amenorrhoea (the absence of menstrual periods) or oligomenorrhoea (infrequent periods) are often the first signs of female hypogonadism. Primary amenorrhoea refers to when menstruation has never occurred in someone of reproductive age. Secondary amenorrhea is defined as no menstruation for more than three months after previous regular menstrual periods.
In primary hypogonadism, where the ovaries fail to produce adequate oestrogen, the lack of oestrogen means a lack of negative feedback on the hypothalamus and pituitary, resulting in increased production of GnRH, LH and FSH. This may be referred to as hypergonadotropic hypogonadism, referring to raised gonadotropins (LH and FSH) and reduced gonad function. On a blood test, LH and FSH will be high, and oestrogen will be low.
Causes of primary hypogonadism include:
- Menopause
- Damage to the ovaries (e.g. surgery, cancer or infections such as mumps)
- Turner’s syndrome (XO)
- Congenital absence of the ovaries
In secondary hypogonadism, the pituitary produces inadequate LH and FSH, which causes understimulation of the ovaries and underproduction of oestrogen. This may be called hypogonadotropic hypogonadism, which refers to reduced gonadotropins (LH and FSH) and reduced output of the gonads (ovaries). On a blood test, LH, FSH, and oestrogen will all be low.
Causes of secondary hypogonadism include:
- Pituitary damage (e.g., tumours, radiotherapy, surgery, or Sheehan syndrome)
- Hyperprolactinemia (raised prolactin suppresses LH and FSH)
- Thyroid pathology (hyperthyroidism or hypothyroidism)
Sheehan’s syndrome is a rare complication of post-partum haemorrhage, where the drop in circulating blood volume leads to avascular necrosis of the pituitary gland. Low blood pressure and reduced perfusion of the pituitary gland lead to ischaemia in the pituitary cells, causing cell death. Sheehan’s syndrome only affects the anterior pituitary gland. Therefore, hormones produced by the posterior pituitary are spared.
The hypothalamus reduces the production of GnRH in response to significant physiological or psychological stress. This leads to hypogonadotropic hypogonadism and amenorrhoea. The hypothalamus responds this way to prevent pregnancy in situations where the body may not be fit for it, for example:
- Excessive exercise (e.g. athletes)
- Low body weight and eating disorders
- Chronic disease
- Psychological stress
Kallman syndrome is a genetic condition causing hypogonadotropic hypogonadism, resulting in failure to start puberty. It is associated with a reduced or absent sense of smell (anosmia).
TOM TIP: There is an essential difference between primary and secondary amenorrhoea and primary and secondary hypogonadism. Primary amenorrhoea refers to never starting menstrual periods. Secondary amenorrhoea refers to the menstrual periods stopping after having previously been regular. Primary hypogonadism relates to the failure of the ovaries. Secondary hypogonadism refers to under-stimulation of the ovaries by LH and FSH from the anterior pituitary.
Polycystic Ovarian Syndrome
Patients with polycystic ovarian syndrome (PCOS) have several hormonal irregularities:
- Relatively high LH and low FSH
- High androgens
- High oestrogen
- Insulin resistance and high insulin levels
Hormonal imbalances start with the abnormal release of gonadotropin-releasing hormone (GnRH). GnRH is normally released in regular pulses. In PCOS, the pulses are irregular, leading to excessive LH and relatively less FSH.
- Excessive LH stimulates the theca cells to produce excessive androgens (e.g., testosterone)
- Inadequate FSH means insufficient follicle development in the ovaries and no ovulation (anovulation)
Insufficient follicle development and inadequate FSH means the granulosa cells do not convert the excess androgens into oestrogen. Androgens build up and are released into the blood. Some of the excess androgens are converted into excess oestrogen by aromatase in adipose tissue (fat tissue).
PCOS causes insulin resistance (the reason is unclear). The pancreas responds to insulin resistance by secreting more insulin, leading to high insulin levels.
Hormonal Contraception
There are two main types of hormonal contraception:
- Combined oral contraceptive pills (containing oestrogen and a progestogen)
- Progestogen-only contraceptives (pills, injections, implants and coils)
Combined oral contraceptive pills prevent pregnancy in three ways:
- Preventing ovulation (this is the primary mechanism of action)
- Progesterone thickens the cervical mucus
- Progesterone inhibits proliferation of the endometrium, reducing the chance of successful implantation
Combined oral contraceptive pills are used for contraception. They are also used to treat:
- Premenstrual syndrome (psychological, emotional and physical symptoms in the days before a period)
- Heavy periods (menorrhagia)
- Painful periods (dysmenorrhoea)
- Endometriosis
Traditional progestogen-only pills (e.g., norethisterone) work mainly by:
- Thickening the cervical mucus
- Altering the endometrium and making it less accepting of implantation
- Reducing ciliary action in the fallopian tubes
The desogestrel pill works mainly by:
- Inhibiting ovulation
- Thickening the cervical mucus
- Altering the endometrium
- Reducing ciliary action in the fallopian tubes
Progestogen-only injections and implants work primarily by inhibiting ovulation.
Hormonal coils (e.g., Mirena coil) work by releasing levonorgestrel (a progestogen) into the local area:
- Thickening cervical mucus
- Altering the endometrium and making it less accepting of implantation
- Inhibiting ovulation in a small number of women
Menopause
Menopause is defined as a permanent end to menstruation. It is a retrospective diagnosis made after a woman has had no periods for 12 months. On average, women experience menopause around the age of 51, although this varies significantly. Menopause is a normal process affecting all women who reach a suitable age.
Postmenopause describes the period from 12 months after the final menstrual period onwards.
Perimenopause refers to the period around menopause, during which the woman may experience vasomotor symptoms and irregular periods. It includes the time leading up to the last menstrual period and the 12 months afterwards. This is typically in women older than 45.
Premature menopause is menopause before the age of 40 years. It is the result of premature ovarian insufficiency.
Perimenopause and menopause are caused by a lack of ovarian follicular function, resulting in changes in the sex hormones associated with the menstrual cycle:
- Oestrogen and progesterone levels are low
- LH and FSH levels are high in response to an absence of negative feedback from oestrogen
The process begins with a decline in the development of the follicles. With less follicle development, there is reduced production of oestrogen. As the level of oestrogen falls in the perimenopausal period, there is reduced negative feedback on the pituitary gland and increasing levels of LH and FSH.
The failing follicular development means ovulation does not occur (anovulation), resulting in irregular menstrual bleeding. Without oestrogen, the endometrium does not thicken, leading to a lack of menstruation (amenorrhoea).
Reduced oestrogen leads to symptoms of:
- Hot flushes
- Emotional lability or low mood
- Premenstrual syndrome
- Irregular periods
- Joint pains
- Heavier or lighter periods
- Vaginal dryness and atrophy
- Reduced libido
Low oestrogen also increases the risk of osteoporosis (oestrogen helps maintain bone density).
Hormone Replacement Therapy
Hormone replacement therapy (HRT) can be used during the perimenopausal and postmenopausal periods to alleviate symptoms associated with a decline in oestrogen levels. Exogenous oestrogen (exo- meaning outside and -genous meaning origin) is taken to alleviate the symptoms. Oestrogen can be given as a tablet (oral), patch (transdermal) or gel (transdermal). Oestrogen can be applied directly to the vagina as a pessary, tablet or cream to help with localised symptoms.
Oestrogen without the balancing effects of progesterone (called unopposed oestrogen) causes the endometrial tissue to proliferate. This can cause endometrial hyperplasia and endometrial cancer. Progesterone balances and modulates the effects of oestrogen, preventing excessive growth of the endometrium. Women who still have a uterus require progesterone alongside the oestrogen when taking HRT. Progesterone can be given as a coil (e.g., Mirena coil), tablet or patch.
Women who have had a hysterectomy (and have had their uterus and endometrium removed) can take oestrogen without progesterone. They have no endometrium and, therefore, no risk of endometrial hyperplasia and cancer.
Medications
GnRH agonists (e.g., goserelin and leuprorelin) are used to shut down the menstrual cycle and the production of oestrogen. They are used to treat oestrogen-receptor-positive breast cancer (where oestrogen is feeding the breast cancer), endometriosis and during in-vitro fertilisation. They initially stimulate the pituitary gland to secrete a large amount of FSH and LH. However, after this initial surge in FSH and LH, there is negative feedback to the hypothalamus, and the natural production of GnRH is suppressed. This causes suppression of oestrogen and the menstrual cycle.
Aromatase inhibitors (e.g., letrozole or anastrozole) are used to reduce oestrogen levels in postmenopausal women with oestrogen-receptor-positive breast cancer. Aromatase is an enzyme found in fat (adipose) tissue that converts androgens to oestrogen. After menopause, the action of aromatase in fat tissue is the primary source of oestrogen. Aromatase inhibitors work by blocking the creation of oestrogen in fat tissue.
Tamoxifen is a selective oestrogen receptor modulator (SERM). Depending on the site of action, it either blocks or stimulates oestrogen receptors. It blocks oestrogen receptors in breast tissue and stimulates oestrogen receptors in the uterus and bones. It is used to treat oestrogen-receptor-positive breast cancer in pre-menopausal women. By stimulating oestrogen receptors in bone, it helps prevent osteoporosis. By stimulating oestrogen receptors in the uterus, it increases the risk of endometrial cancer.
Fulvestrant is a selective oestrogen receptor downregulator. It works by blocking and reducing the number of oestrogen receptors. It is used to treat oestrogen-receptor-positive breast cancer.
Mifepristone is a progesterone receptor antagonist (it blocks progesterone receptors). It is for termination of pregnancy and to resolve a missed miscarriage (where the products of conception remain in the uterus, but the pregnancy is not viable).
Ulipristal acetate is a selective progesterone receptor modulator. Depending on the tissue, it blocks or partially stimulates progesterone receptors. It delays ovulation and is used for emergency contraception.
Last updated August 2024
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