Physiology of the menstrual cycle

The external manifestation of a normal menstrual cycle is the presence of

regular vaginal bleeding. This occurs as a result of the shedding of the
endometrial lining following failure of fertilization of the oocyte or failure of
implantation. The cycle depends on changes occurring after puberty within
the ovaries and fluctuation in ovarian hormone levels, which are themselves
controlled by the pituitary and hypothalamus within the hypothalamo–pituitary–
ovarian axis (HPO). In situations of DSD or hormonal abnormalities,
menstruation may not begin.

The hypothalamus
The hypothalamus in the forebrain secretes the peptide hormone
gonadotrophin-releasing hormone (GnRH), which in turn controls pituitary
hormone secretion. GnRH must be released in a pulsatile fashion to stimulate
pituitary secretion of luteinizing hormone (LH) and follicle-stimulating
hormone (FSH).

The pituitary gland

GnRH stimulation of the basophil cells in the anterior pituitary gland causes
synthesis and release of the gonadotrophic hormones FSH and LH. This
process is modulated by the ovarian sex steroid hormones oestrogen and
progesterone. Low levels of oestrogen have an inhibitory effect on LH
production (negative feedback), whereas high levels of oestrogen will
increase LH production (positive feedback). The mechanism of action for the
positive feedback effect of oestrogen involves an increase in GnRH receptor
concentrations, while the mechanism of the negative feedback effect is
uncertain. The high levels of circulating oestrogen in the late follicular phase
of the ovary act via the positive-feedback mechanism to generate a
periovulatory LH surge from the pituitary.
The clinical relevance of these mechanisms is seen in the use of the
combined oral contraceptive pill, which artificially creates a constant serum
oestrogen level in the negative-feedback range, inducing a correspondingly
low level of gonadotrophin hormone release.
Unlike oestrogen, low levels of progesterone have a positive-feedback effect
on pituitary LH and FSH secretion (as seen immediately prior to ovulation)
and contribute to the LH and FSH surge. High levels of progesterone, as seen
in the luteal phase, inhibit pituitary LH and FSH production. Positive-
feedback effects of progesterone occur via increasing sensitivity to GnRH in
the pituitary. Negative-feedback effects are generated through both
decreased GnRH production from the hypothalamus and decreased sensitivity
to GnRH in the pituitary. It is known that progesterone can only have these
effects on gonadotropic hormone release after priming by oestrogen .

The ovary
Starting at menarche, the primordial follicles containing oocytes, arrested at
the first prophase step in meiotic division, will start to activate and grow in a
cyclical fashion, causing ovulation and subsequent menstruation in the event
of non-fertilization. In the course of a normal menstrual cycle, the ovary will
go through three phases: follicular, ovulatory and luteal.
Figure 3.1 Hypothalamus–pituitary axis. (E2, oestrogen; FSH, follicle-
stimulating hormone; GnRH, gonadotrophin-releasing hormone; LH, luteinizing
hormone; P4, progesterone.)

Follicular phase
The initial stages of follicular development are independent of hormone
stimulation. However, follicular development will fail at the preantral stage,
and follicular atresia will ensue if pituitary hormones LH and FSH are absent.
FSH levels rise in the first days of the menstrual cycle, when oestrogen,
progesterone and inhibin levels are low. This stimulates a cohort of small
antral follicles on the ovaries to grow.
As the follicles grow and oestrogen secretion increases, there is negative
feedback on the pituitary to decrease FSH secretion. This assists in the
selection of one follicle to continue in its development towards ovulation –
the dominant follicle. In the ovary, the follicle that has the most efficient
aromatase activity and highest concentration of FSH-induced LH receptors
will be the most likely to survive as FSH levels drop, while smaller follicles
will undergo atresia.
Ovulation
By the end of the follicular phase, which lasts an average of 14 days, the
dominant follicle has grown to approximately 20 mm in diameter. As the
follicle matures, FSH induces LH receptors on the granulosa cells to
compensate for lower FSH levels and prepare for the signal for ovulation.
Production of oestrogen increases until it reaches the necessary threshold to
exert a positive feedback effort on the hypothalamus and pituitary to cause the
LH surge. This occurs over 24–36 hours, during which time the LH-induced
luteinization of granulosa cells in the dominant follicle causes progesterone to
be produced, adding further to the positive feedback for LH secretion and
causing a small periovulatory rise in FSH. Androgens, synthesized in the theca
cells, also rise around the time of ovulation, and this is thought to have an
important role in stimulating libido, ensuring that sexual activity is likely to
occur at the time of greatest fertility.
The LH surge is one of the best predictors of imminent ovulation, and this
is the hormone detected in urine by most over-the-counter ‘ovulation
predictor’ tests. The LH surge has another function in stimulating the
resumption of meiosis in the oocyte just prior to its release. The physical
ovulation of the oocyte occurs after breakdown of the follicular wall takes
place under the influence of LH, FSH and proteolytic enzymes, such as
plasminogen activators and prostaglandins (PGs),

Luteal phase
After the release of the oocyte, the remaining granulosa and theca cells on the
ovary form the corpus luteum (CL). The granulosa cells have a vacuolated
appearance with accumulated yellow pigment, hence the name CL (‘yellow
body’).
Ongoing pituitary LH secretion and granulosa cell activity ensure a supply
of progesterone, which stabilizes the endometrium in preparation for
pregnancy. Progesterone levels are at their highest in the cycle during the luteal
phase. This also has the effect of suppressing FSH and LH secretion to a level
that will not produce further follicular growth in the ovary during that cycle.
 The luteal phase lasts 14 days in most women, without great variation. In
the absence of beta- human chorionic gonadotrophin (βhCG) being produced
from an implanting embryo, the CL will regress in a process known as
luteolysis. The mature CL is less sensitive to LH, produces less progesterone
and will gradually disappear from the ovary. The withdrawal of progesterone
has the effect on the uterus of causing shedding of the endometrium and thus
menstruation. Reduction in levels of progesterone, oestrogen and inhibin
feeding back to the pituitary cause increased secretion of gonadotrophic
hormones, particularly FSH. New preantral follicles begin to be stimulated
and the cycle begins anew.

The endometrium
The hormone changes effected by the HPO axis during the menstrual cycle will
occur whether the uterus is present or not. However, the specific secondary
changes in the uterine endometrium give the most obvious external sign of
regular cycles.

The proliferative phase

The endometrium enters the proliferative phase after menstruation, when
glandular and stromal growth begin. The epithelium lining the endometrial
glands changes from a single layer of columnar cells to a pseudostratified
epithelium with frequent mitoses. Endometrial thickness increases rapidly,
from 0.5 mm at menstruation to 3.5–5 mm at the end of the proliferative phase.

The secretory phase

After ovulation (generally around day 14), there is a period of endometrial
glandular secretory activity. Following the LH surge, the oestrogen-induced
cellular proliferation is inhibited and the endometrial thickness does not
increase any further. However, the endometrial glands will become more
tortuous, spiral arteries will grow and fluid is secreted into glandular cells and
into the uterine lumen. Later in the secretory phase, progesterone induces the
formation of a temporary layer, known as the decidua, in the endometrial
stroma. Histologically, this is seen as occurring around blood vessels.
Stromal
cells show increased mitotic activity, nuclear enlargement and generation of a
basement membrane.
Apical membrane projections of the endometrial epithelial cells, known as
pinopodes, appear after day 21–22 and appear to be a progesterone-dependent
stage in making the endometrium receptive for embryo implantation.

Figure 3.2 Changes in hormone levels, endometrium and follicle development

during the menstrual cycle.
Figure 3.3 Tissue sections of normal endometrium during proliferative (A) and
secretory (B) phases of the menstrual cycle.

Figure 3.4 Photomicrograph of endometrial pinopods from the implantation

window.

Menstruation
Menstruation (day 1) is the shedding of the ‘dead’ endometrium and ceases as
the endometrium regenerates (which normally happens by day 5–6 of the
cycle). Immediately prior to menstruation, three distinct layers of
endometrium can be seen. The basalis is the lower 25% of the
endometrium, which will
remain throughout menstruation and shows few changes during the menstrual
cycle.
A fall in circulating levels of oestrogen and progesterone approximately 14
days after ovulation leads to loss of tissue fluid, vasoconstriction of spiral
arterioles and distal ischaemia. This results in tissue breakdown and loss of
the upper layers, along with bleeding from fragments of the remaining
arterioles, seen as menstrual bleeding. Enhanced fibrinolysis reduces clotting.
Vaginal bleeding will cease after 5–10 days as arterioles vasoconstrict and
the endometrium begins to regenerate. Haemostasis in the uterine endometrium
is different from haemostasis elsewhere in the body as it does not involve the
processes of clot formation and fibrosis.
Endometrial repair involves both glandular and stromal regeneration and
angiogenesis to reconstitute the endometrial vasculature.

Puberty and secondary sexual development

Normal puberty
Puberty is the process of reproductive and sexual development and
maturation that changes a child into an adult. During childhood, the HPO axis
is suppressed and levels of GnRH, FSH and LH are very low. From the age of
8– 9 years GnRH is secreted in pulsations of increasing amplitude and
frequency. These are initially sleep-related, but as puberty progresses, these
extend throughout the day. This stimulates secretion of FSH and LH by the
pituitary glands, which in turn triggers follicular growth and steroidogenesis
in the ovary. The oestrogen produced by the ovary then initiates the physical
changes of puberty. The exact mechanism determining the onset of puberty is
still unknown, but it is influenced by many factors including race, heredity,
body weight and exercise. Leptin plays a permissive role in the onset of
puberty.
The physical changes occurring in puberty are breast development
(thelarche), pubic and axillary hair growth awakening of adrenal glands
(adrenarche), growth spurt and onset of menstruation (menarche).
The first physical signs of puberty are breast budding and this occurs 2–3
years before menarche. The appearance of pubic hair is dependent on the
secretion of adrenal androgens and is usually after thelarche. In addition to
increasing levels of adrenal and gonadal hormones, growth hormone
secretion also increases, leading to a pubertal growth spurt. The mean age of
menarche is 12.8 years and it may take over 3 years before the menstrual
cycle establishes a regular pattern. Initial cycles are usually anovulatory and
can be unpredictable and irregular. The absence of menstruation is called
amenorrhoea and may be primary or secondary). Pubertal development was
described by Tanner and the stages of breast and pubic hair development are
often referred to as Tanner stages.

Precocious puberty
This is defined as the onset of puberty before the age of 8 in a girl or 9 in a
boy. It is classified as either central or peripheral. Central precocious puberty
is gonadotrophin dependent. The aetiology is often unknown, although up to
25% are due to central nervous system (CNS) malformations or brain tumours.
Peripheral precocious puberty, which is gonadotrophin independent, is
always pathological and can be caused by oestrogen secretion, such as
exogenous ingestion or a hormone-producing tumour.

Delayed puberty
When there are no signs of secondary sexual characteristics by the age of 14
years this is termed delayed puberty. It is due to either a central defect
(hypogonadotrophic hypogonadism) or a failure of gonadal function
(hypergonadotrophic hypogonadism), which are described below.

Disorders of sexual development

DSD are conditions where the sequence of events described above does not
happen. The clinical consequences of this depend upon where within the
sequence the variation occurs. DSD may be diagnosed at birth with
ambiguous or abnormal genitalia, but may also be seen at puberty in girls
who present with primary amenorrhoea or increasing virilization.

Disorders of menstrual regularity

Amenorrhoea and oligomenorrhoea
Amenorrhoea is defined as the absence of menstruation for more than 6
months in the absence of pregnancy in a woman of fertile age, and
oligomenorrhoea is defined as irregular periods at intervals of more than 35
days, with only 4–9 periods a year. The causes may be hypothalamic,
pituitary, ovarian or endometrial, and both amenorrhoea and
oligomenorrhoea may be primary or secondary.

Amenorrhoea
• Primary amenorrhoea is when girls fail to menstruate by 16 years of age.
• Secondary amenorrhoea is absence of menstruation for more than 6
months in a normal female of reproductive age that is not due to
pregnancy, lactation or the menopause.

Hypothalamic disorders
Hypothalamic disorders will give rise to hypogonadotrophic hypogonadism,
with the following causes:

• Excessive exercise, weight loss and stress.

• Hypothalamic lesions (craniopharyngioma, glioma), which can compress
hypothalamic tissue or block dopamine.
• Head injuries.
• Kallman’s syndrome (X-linked recessive condition resulting in deficiency
in GnRH causing underdeveloped genitalia).
• Systemic disorders including sarcoidosis, tuberculosis resulting in an
infiltrative process in the hypothalamo-hypophyseal region.
• Drugs: progestogens, HRT or dopamine antagonists.

Pituitary disorders
Pituitary disorders will also give rise to hypogonadotrophic hypogonadism,
with the following causes:

• Adenomas, of which prolactinoma is most common.

• Pituitary necrosis (e.g. Sheehan’s syndrome, due to prolonged hypotension
following major obstetric haemorrhage).
• Iatrogenic damage (surgery or radiotherapy).
• Congenital failure of pituitary development.

Ovarian disorders
Anovulation is often due to polycystic ovary syndrome (PCOS), described
below. Ovarian failure is the cause of hypergonadotrophic hypogonadism.
Premature ovarian failure (POF) is defined as cessation of periods before 40
years of age.

Endometrial disorders
Primary amenorrhoea may result from Müllerian defects in the genital tract
including an absent uterus, or outflow tract abnormalities, leading to a
haematocolpos. Secondary amenorrhoea may result from scarring of the
endometrium called Asherman syndrome.
Findings from the history should guide the examination. A general
inspection of the patient should be carried out to assess body mass index
(BMI), secondary sexual characteristics (hair growth, breast development
using Tanner scores) and signs of endocrine abnormalities (hirsutism, acne,
abdominal striae, moon face, skin changes). If the history is suggestive of a
pituitary lesion, an assessment of visual fields is indicated. External genitalia
and a vaginal examination should be performed to detect structural outflow
abnormalities or demonstrate atrophic changes consistent with hypo-
oestrogenism.

Investigation of amenorrhoea/oligomenorrhoea

Findings from the history and examination should guide the choice and order of
investigations. A pregnancy test should be carried out if the patient is
sexually active. Blood can be taken for LH, FSH and testosterone; raised LH
or raised testosterone could be suggestive of PCOS; raised FSH may be
suggestive of POF. A raised prolactin level may indicate a prolactinoma.
Thyroid function should be checked if clinically indicated. An ultrasound
scan can be useful in detecting the classical appearances of polycystic ovaries
and magnetic resonance imaging (MRI) of the brain should be carried out if
symptoms are consistent with a pituitary adenoma. Hysteroscopy is not
routine, but is a suitable investigation where Asherman or cervical stenosis is
suspected. Karyotyping is diagnostic of Turner’s and other sex chromosome
abnormalities.

Table 3.3 Management of amenorrhoea/oligomenorrhoea

Findings from the history and examination should guide the choice and order of
investigations. A pregnancy test should be carried out if the patient is
sexually active. Blood can be taken for LH, FSH and testosterone; raised LH
or raised testosterone could be suggestive of PCOS; raised FSH may be
suggestive of POF. A raised prolactin level may indicate a prolactinoma.
Thyroid function should be checked if clinically indicated. An ultrasound
scan can be useful in detecting the classical appearances of polycystic ovaries
and magnetic resonance imaging (MRI) of the brain should be carried out if
symptoms are consistent with a pituitary adenoma. Hysteroscopy is not
routine, but is a suitable investigation where Asherman or cervical stenosis is
suspected. Karyotyping is diagnostic of Turner’s and other sex chromosome
abnormalities.

Polycystic ovary syndrome

PCOS is a syndrome of ovarian dysfunction along with the cardinal features
of hyperandrogenism and polycystic ovary morphology. The prevalence of
polycystic ovaries seen on ultrasound is around 25% of all women but is not
always associated with the full syndrome. Clinical manifestations include
menstrual irregularities, signs of androgen excess (e.g. hirsutism and acne)
and obesity. Elevated serum LH levels, biochemical
evidence of hyperandrogenism and raised insulin resistance are also
common features.
PCOS is associated with an increased risk of type 2 diabetes and
cardiovascular events. It affects around 5–10% of women of reproductive
age.
The aetiology of PCOS is not completely clear, although the frequent
familial trend points to a genetic cause.

Clinical features
• Oligomenorrhoea/amenorrhoea in up to 75% of patients,
predominantly related to chronic anovulation.
• Hirsutism.
• Subfertility in up to 75% of women.
• Obesity in at least 40% of patients.
• Acanthosis nigricans (areas of increased velvety skin pigmentation occur
in the axillae and other flexures).
• May be asymptomatic.

Diagnosis
Patients must have two out of the three features below:

• Amenorrhoea/oligomenorrhoea.
• Clinical or biochemical hyperandrogenism.
• Polycystic ovaries on ultrasound. The ultrasound criteria for the
diagnosis of a polycystic ovary are eight or more subcapsular follicular
cysts <10 mm in diameter and increased ovarian stroma. While these
findings support a diagnosis of PCOS, they are not by themselves
sufficient to identify the syndrome.

Management
Management of PCOS involves the following:
• Combined oral contraceptive pill (COCP) to regulate menstruation. This
also increases sex hormone-binding globulin, which will help reduce
androgenic symptoms.
• Cyclical oral progesterone: used to regulate a withdrawal bleed.
• Clomiphene: this can be used to induce ovulation where subfertility is a
factor.
• Lifestyle advice: dietary modification and exercise is appropriate in these
patients as they are at an increased risk of developing diabetes and
cardiovascular disease later in life. Aerobic exercise has been shown to
improve insulin resistance.
• Weight reduction.
• Ovarian drilling, a laparoscopic procedure to destroy some of the
ovarian stroma that may prompt ovulatory cycles.
• Treatment of hirsutism/androgenic symptoms:
• eflornithine cream (Vaniqua™) applied topically;
• cyproterone acetate (an antiandrogen contained in the
Dianette™ contraceptive pill, sometimes used alone);
• metformin: this is beneficial in a subset of patients with PCOS, those
with hyperinsulinaemia and cardiovascular risk factors. It improves
parameters of insulin resistance, hyperandrogenaemia, anovulation and
acne in PCOS, and may aid weight loss. It is less effective than
clomiphene for ovulation induction and does not improve pregnancy
outcome;
• GnRH analogues with low-dose HRT: this regime should be reserved
for women intolerant of other therapies;
• surgical treatments (e.g. laser or electrolysis).

Premenstrual syndrome
Premenstrual syndrome (PMS) is the occurrence of cyclical somatic,
psychological and emotional symptoms that occur in the luteal
(premenstrual) phase of the menstrual cycle and resolve by the time
menstruation ceases. Premenstrual symptoms occur in almost all women of
reproductive age. In 3– 60% symptoms are severe, causing disruption to
everyday life, in particular interpersonal relationships.

Aetiology
The precise aetiology of PMS is unknown, but cyclical ovarian activity and
the effects of oestradiol and progesterone on certain neurotransmitters,
including serotonin, appear to play a role.

History and examination

The patient is likely to complain of some or all of the following: bloating
cyclical weight gain, mastalgia, abdominal cramps, fatigue, headache,
depression, irritability. The cyclical nature of PMS is the cornerstone of the
diagnosis. A symptom chart, to be filled in by the patient prospectively,
may help.

Management
The management of PMS is depicted below.
Algorithm for the treatment of premenstrual syndrome (PMS). (GP, general
practitioner; GnRH, gonadotrophin-releasing hormone; HRT, hormone
replacement therapy; NAPS, National Association for Premenstrual
Syndrome.) (Adapted with permission from Guidelines for the National
Association for Premenstrual Syndrome, www.pms.org.uk.)

• Simple therapies: include stress reduction, alcohol and caffeine limitation

and exercise.
• Medical treatments:
• COCP: the most effective regime appears to be bicycling or tricycling
pill packets (i.e. taking two or three packets in a row without a
scheduled break);
• transdermal oestrogen: this has been shown to significantly reduce PMS
symptoms, by overcoming the fluctuations of the normal cycle;
• GnRH analogues are a very effective treatment for PMS as they turn off
ovarian activity. To reduce the risk of osteoporosis it is recommended
that a continuous combined form of hormone replacement therapy is
administered concurrently;
• selective serotonin-reuptake inhibitors (SSRIs): there is good evidence
that this group of drugs significantly improves PMS.
• Hysterectomy with bilateral salpingo-oopherectomy: this procedure
obviously completely removes the ovarian cycle. It should only be
performed if all other treatments have failed. It is essential for such
patients to have a preoperative trial of GnRH analogue as a ‘test’ to
ensure that switching off ovarian function (by removing the ovaries at
hysterectomy) will indeed cure the problem.
• Vitamins: initial studies suggest that magnesium, calcium and isoflavones
and vitamin B6 may be useful in treating PMS.
• Alternative therapies:
• initial results of St John’s Wort are promising, particularly in improving
mood. Although Evening Primrose oil is commonly used, there is no
evidence to support this treatment for PMS;
• cognitive-behavioural therapy (CBT): CBT appears to be particularly
effective when combined with SSRIs.
DISORDER OF MENSTRUAL BLEEDING

Introduction
Disorders of menstrual bleeding, now termed AUB, are one of the most
common reasons for women to attend their general practitioner (GP) and,
subsequently, a gynaecologist. Although rarely life threatening, menstrual
disorders can cause major social, psychological and occupational upset.
There are several types of abnormal bleeding and their terminology should
be known. Heavy menstrual bleeding (HMB), intermenstrual bleeding
(IMB), postcoital bleeding (PCB) and postmenopausal bleeding (PMB)
should be investigated and treated. Initial investigations for each include
speculum examination of the cervix, with swabs for microbiology and
cervical smear if indicated, and transvaginal ultrasound scan (TVUSS) and
endometrial biopsy (EB) as necessary. Further to this, outpatient
hysteroscopy and biopsy may be indicated.
There are several classification systems for AUB, some of which link
symptoms to pathology. Such systems help clinicians to adopt a similar
categorization of the pathology they are seeing, which helps audit and
research.