FEMALE REPRODUCTIVE SYSTEM

DR ABOBARIN OLUFUNMILAYO

FEMALE REPRODUCTIVE SYSTEM

• VULVA
• VAGINA
• CERVIX
• UTERUS
• FALLOPIAN TUBE
• OVARY

EMBRYOLOGY

• The gonadal anlage, (a swelling on the embryonic urogenital ridge) is initially in an indifferent state. It eventually develops into the urogenital system.
• The sex chromosomes and the autosomes in the gonadal stromal cells determine whether the gonad will develop into the male or female.
• If the gonadal stroma is male, the testis determining gene (on the Y chromosome)interacts with other components of the primitive gonad to initiate formation of SEMINIFEROUS TUBULES.
• Ovary develops if the gonadal stroma is female and there is no stimulus to form a testis.

EMBRYOLOGY

• The paramesonephric or mullerian ducts(paired) develop into the fallopian tubes, uterus and vaginal wall.
• The mesonephric ducts or the wolffian ducts regress in the female or remain as vestigial rests(may form cysts in the cervix or vagina).
• Wolffian ducts differentiate into vas deferens, epididymis and seminal vesicle if stimulated by testosterone secreted by the Leydig cells.

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GENITAL INFECTIONS�

Sexually transmitted

Non sexually transmitted infections.

SEXUALLY TRANSMITTED INFECTIONS

May be

A)Bacterial infections

Gonorrhoea

Syphilis

Granuloma inguinale

Chancroid

Gardnerella

Mycoplasma

Chlamydia

PELVIC INFLAMMATORY DISEASE

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GENITAL INFECTIONS

• GONORRHOEA
• Caused by Neisseria gonorrhoea, a Gram negative diplococcus.
• Sexually transmitted
• A frequent cause of acute salpingitis and pelvic inflammatory disease
• Infection ascends through the cervix, to the endometrial cavity (acute endometritis),to the fallopian tube (acute salpingitis).it may spread to the ovary sometimes causing a TUBOOVARIAN ABSCESS.

GENITAL INFECTIONS

• COMPLICATIONS(gonorrhoea);
• The organism induces purulent inflammatory reactions at all sites of infections(endometrium, fallopian tubes etc).these reactions rarely completely resolve and leaves behind dense fibrous adhesions and distortion of the organs especially the fallopian tube. this is a cause of infertility.

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GENITAL INFECTIONS

• SYPHILIS
• Caused by Treponema pallidum, which is a thin motile spiral shaped bacterium. it may be sexually transmitted or acquired by the foetus transplacentally(congenital syphilis).
• The organism can penetrate normal mucosal surface or small cuts in the skin.
• Untreated syphilis has three stages:

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GENITAL INFCTIONS

• Primary syphilis: appears 3 weeks at its portal of entry, characterised by presence of a painless indurated papule.
• Secondary syphilis: occurs after several weeks to months.
• It is characterised by low grade fever, maculopapular rash, malaise, lymphadenopathy and syphilitic warts(condyloma lata).
• Tertiary syphilis; develops thereafter and may entail severe damage to the cardiovascular(aortitis) and nervous systems(syphilitic granulomas known as gummas)

GENITAL INFECTIONS

• CHLAMYDIA
• Aetiology is Chlamydia trachomatis which has several serotypes.
• Serotypes D through K(D,E,F,G,H,I,J,K) cause the more common genital infections especially in the cervix and endocervix(non gonococcal urethritis,cervicitis,PID). This may be complicated by ascending infections of the endometrium ,fallopian tube and ovary.
• Serotypes L1,L2,L3 cause lymphogranuloma venereum (LGV)which is endemic in tropical countries.

GENITAL INFECTIONS

• CHLAMYDIA(CONTD)
• The infection is characterised by a painless vesicle at the site of inoculation which is often unnoticed and heals rapidly. In the second stage of infection, inguinal lymph nodes are enlarged and may rupture to form suppurative fistulas. Perirectal lymph nodes may be enlarged in women.
• The third stage may last several years. Scarring causes lymphatic obstruction resulting genital elephantiasis and rectal strictures

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GENITAL INFECTIONS

• PELVIC INFLAMMATORY DISEASE (PID)
• PID refers to infection of pelvic organs by a variety of organisms which extends beyond the uterine corpus.
• The ascent of the infection results in bilateral acute salpingitis, pyosalpinx and tuboovarian abscesses.
• N.gonorrhoea and chlamydia are the most common agents but most infections are usually polymicrobial.
• It is commoner among sexually promiscuous women than in monogamous women. It ocassionally occurs after post partum endometritis or as a complication of endometrial curretage,in this situation PID is caused by Staphylococcus, strept ,coliforms, Clostridium perfringens

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GENITAL INFECTIONS

• Presentation; l ower abdominal pain.
• Examination; bilateral adnexal tenderness, marked discomfort when the cervix is manipulated(Chandeliers sign)
• Complications
• Rupture of tuboovarian abscess which can result life threatening peritonitis.
• Infertility from scarring of the healed fallopian tubes
• Increased risk of ectopic pregnancy
• Intestinal obstruction from fibrous bands and adhesions.

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GENITAL INFECTIONS

• VIRAL INFECTIONS
• Condyloma acuminatum.
• Herpesvirus
• Cytomegalovirus
• Molluscum contagiosum

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GENITAL INFECTIONS

• CONDYLOMA ACUMINATUM
• Also known as benign genital warts .
• Aetiology; Low risk oncogenic human papilloma virus types 6 and 11.
• May be solitary lesions but more frequently multifocal and involve the vulvar, vagina, perineal and the perianal regions; it may also involve the urethra, bladder and the rectum. histologically,they show papillomatous squamous proliferation with koilocytes(epithelial cells with a perinuclear halo and wrinkled nucleus)

GENITAL INFECTIONS

• HERPESVIRUS
• Aetiology: herpes virus types 1 and 2.
• Infection involves the cervix,vagina,vulva.
• Herpes simplex virus (HSV)type 1 typically cause oropharyngeal infection while HSV type 2 typically infects the genital mucosa and skin.
• However, HSV 1 can be detected in genital infection while HSV2 may also be detected in the mouth in individuals that engage in oral sex.
• Patient may present with papules 3-7 days after infection, then as vesicles which become painful coalescent ulcers if the lesion involve the skin.

GENITAL INFECTIONS

• If the infection is in the vagina or cervix, patient presents with purulent discharge .
• Lesions heal spontaneously within 1-3 weeks .
• During the acute stage of the infection the virus migrates to the lumbosacral nerve ganglia where it establishes a latent infection which can be reactivated by any decrease in immune function such as stress, trauma, ultraviolet radiation, hormonal changes such as pregnancy, immunosuppressed states such as HIV (AIDS) infection.
• Smears of exudate from the skin and mucosal lesions show HSV cytopathic changes consisting of multinucleated giant squamous cells containing eosinophilic to basophilic viral inclusions with ground glass appearance.

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GENITAL INFECTIONS

• MOLLUSCUM CONTAGIOSUM
• Aetiology: pox virus,molluscum contagiosum virus (MCV)types 1,2,3,4.
• MCV 1 is most prevalent while MCV 2 is the most often sexually transmitted
• Infection can occur in young children through direct contact or through shared articles eg towel.
• .

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GENITAL INFECTIONS

• Molluscum contd
• MCV infections in adults is most often sexually transmitted and affects the genitals ,lower abdomen and inner thighs.
• Diagnosed clinically as pearly dome shaped pappule with central dimple,these lesions exude cheesy material.
• Histology:
• Coin like eosinophilic bodies (molluscum bodies) which are large cytoplasmic viral inclusions are seen in infected epithelial cells.

GENITAL INFECTIONS

NON SEXUALLY TRANSMITTED INFECTIONS

Tuberculosis - tuberculous salpingitis

- tuberculous endometritis.

Candidiasis.

Actinomycosis.

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GENITAL INFECTIONS

• CANDIDIASIS
• Aetiology :Candida albicans
• 10% of women generally are asymptomatic carriers of fungi in the vulva and vagina; of these candida albicans is the commonest agent. Only 2% of these present with candidal vulvovaginitis
• Diabetes mellitus, oral contraceptive use and pregnancy make women more susceptible to candidiasis.

GENITAL INFECTIONS

• Examination reveals small white firmly adherent plaques on the mucus membranes, these plaques are composed of desquamated necrotic epithelial cells, cellular debris, bacterial flora, candidal spores, pseudohyphae.
• Untreated infections usually wax and wane and often disappear following delivery.

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GENITAL INFECTIONS

• ACTINOMYCOSIS
• Aetiology: Actinomyces isreali
• Initially uncommon but increasingly associated with the use of intrauterine devices(IUDs).
• Actinomyces isreali is a Gram positive branching rod (filamentous bacteria)found in 4% of normal individuals. Organism enters the uterine cavity through the tail of the intrauterine device, it ascends the fallopian tube, ovary and broad ligament,it may form a tuboovarian abscess.
• .

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GENITAL INFECTIONS

• Suppurating lesions display drainage tracts that contain dense microcolonies of organisms(sulphur granules)
• Actinomycosis results in extensive fibrosis and scarring of the female genital tract

VULVA

• The vulva is composed of the mons pubis,labia majora and minora,clitoris and the vestibule.
• The urethral opening is flanked by paired external openings of the SKENE s glands.
• BARTHOLINS glands are mucus secreting glands present immediately posterolateral to the introitus

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DISEASES OF THE VULVA

• Diseases of the vulva are uncommon.
• Most skin lesions(ranging from epidermal inclusion cysts to skin cancers) that occur on the skin in other parts of the body also occur in the vulva; Vulvar specific lesions however include Bartholins cyst, non neoplastic epithelial disorders, benign exophytic lesions like condyloma acuminatum and tumours of the vulva.

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BARTHOLINS GLAND CYST

Bartholins glands produce clear mucus secretion that lubricates the vestibular surface.

Bartholins gland ducts are prone to obstruction and subsequent abscess formation.

The cyst formed may become infected and form an abscess.

VULVAR TUMOURS

• Carcinoma of the vulva is uncommon, it accounts for 3% of all female genital cancers and occurs mainly in women over years.
• Squamous cell carcinoma is the most common histologic type ;this can be divided into ;

A)Keratinising squamous cell carcinoma which is unrelated to HPV infection and constitute over 70% of all cases. The precursor lesion is the differentiated Vulvar Intraepithelial Neoplasm(VIN) which occurs in older women in a background of leukoplakia

B)Warty and basaloid type which are associated with high risk HPV infection(HPV 16), this constitutes less than 25% of all cases. Precursor lesion is the undifferentiated or classic VIN which occurs in women of child bearing age who are sexually active and are at risk of HPV infection.

VAGINA

• DEVELOPMENTAL ANOMALIES
• PRIMARY TUMOURS

DEVELOPMENTAL ANOMALIES

• Some developmental anomalies are related to in utero exposure to Diethylstilbesterol (DES) which was used in the 1940s through 1960s to prevent threatened abortion. Females whose mothers took DES while pregnant developed ;

1)SEPTATE or double vagina: which arises as a result of failure of fusion of the mullerian duct(uterus didelphys).

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DEVELOPMENTAL ANOMALIES

2) VAGINAL ADENOSIS:

• The vagina and the outer part of the cervix in utero are initially covered by columnar (endocervical type) of epithelium. this is normally replaced by squamous epithelium advancing up from the urogenital sinus.
• With in utero exposure to DES, there may be persistence of this columnar epithelium in adult life seen grossly as red granular patches different from the surrounding pale pink vaginal mucosa. This is known as VAGINAL ADENOSIS. Females with vaginal adenosis usually develop clear cell adenocarcinoma of the vagina during their teens or young adult women.

DEVELOPMENTAL ANOMALIES

• GARTNER DUCT CYST
• Lesions found along the lateral walls of the vagina, they are derived from the wolffian (mesonephric) duct rests.

PRIMARY TUMOURS OF THE VAGINA

• SQUAMOUS CELL CARCINOMA
• Squamous cell carcinoma accounts for over 90% of all vaginal malignancies, it is associated with high risk HPV infection.
• It is a disease of older women peak between 60 and 70 years .
• Vaginal squamous cell carcinoma may develop some years after vulval or cervical squamous cell carcinoma.
• It arises from a premalignant lesion known as VAGINAL INTRAEPITHELIAL NEOPLASIA(VAIN).

EMBRYONAL RHABDOMYOSARCOMA�(SARCOMA BOTRYOIDES)�

• Greek word botrys-grapes
• It is an uncommon primary vaginal tumour in female infants and girls less than 5years.
• Tumour usually presents as polypoid masses in the vagina resembling a bunch of grapes.
• Histologically, tumour cells are small, they have oval nuclei with small protusions of the cytoplasm from one end resembling a tennis racket. Rarely cross striations may be seen(these are indicative of smooth muscle differentiation.

CERVIX

• Inflammatory conditions
• -acute cervicitis
• -chronic cervicitis
• Benign tumours
• -endocervical polyp
• -cervical leiomyomas
• Malignant tumours
• Squamous cell carcinoma
• Cervical adenocarcinoma

ACUTE AND CHRONIC CERVICITIS

• CERVICITIS; inflammation of the cervix which is related to the constant exposure of the bacterial flora in the vagina.
• At menarche oestrogen production by the ovary stimulates maturation of the squamous epithelium of the cervix and vagina with production of intracellular glycogen. When these cells are shed ,the glycogen becomes a substrate for various organisms (aerobes and anaerobes) especially lactobacilli.

ACUTE AND CHRONIC CERVICITIS

• Lactobacilli produce ;
• A)lactic acid responsible for maintaining the vagina acidity (pH 4.5).
• B)Hydrogen peroxide .

Any factor that interferes with normal lactobacilli homeostasis (that reduces bacilli population or interfere with hydrogen peroxide production)in the vagina .This interference enhances the overgrowth of other vaginal aerobes and anaerobes such as Streptococcus, Staphylococcus and can lead to cervicitis. these may be;

Bleeding

Sexual intercourse

Vaginal douching

Antibiotic therapy

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ACUTE AND CHRONIC CERVICITIS

• Exogenously acquired organisms are also aetiological agents of acute and chronic cervicitis. these include
• A)Sexually transmitted agents such as Chlamydia trachomatis, Neisseria gonorrhoea, Herpes simplex type 2.
• B) Organisms introduced by foreign bodies such as residual fragments of tampoons, pessaries etc

ACUTE AND CHRONIC CERVICITIS

• In acute cervicitis, the cervix is red, swollen and oedematous with copious pus dripping from the external os.
• Histologically, theres extensive infiltration of tissues by polymorphonuclear leucocytes and stromal oedema
• Chronic cervicitis is characterised by hyperaemia of the cervical mucosa with erosions. Histologically, the stroma is infiltrated by lymphocytes and plasma cells.
• Marked cervical inflammation produces reparative and reactive changes of the epithelium and shedding of atypical appearing squamous cells constituting a diagnostic dilema which may be a bit difficult to differentiate from cervical neoplasia

ENDOCERVICAL POLYP

• Endocervical polyps are the most common cervical growths, they vary from small sessile bumps to large polypoid masses that may protude through the cervical os. They appear as single smooth or lobulated masses.
• Histologically, they are composed of loose fibromyxomatous stroma covered by mucus secreting endocervical glands.
• They manifest as irregular vaginal bleeding or spotting.
• Simple curettage or surgical excision is curative.

CERVICAL LEIOMYOMAS

• Leiomyomas also occur in the cervix and are histologically similar to uterine leiomyomas.
• They can bleed or prolapse into the endocervical canal leading to uterine contractions and pain and resemble the early phases of labour.

MALIGNANT TUMOURS OF THE CERVIX

• CARCINOMA OF THE CERVIX
• Cancer of the cervix is the third most common cancer in women worldwide. It was the leading cause of death among women in the united states about 50 years ago. However, death rates have declined worldwide because of effective screening early diagnosis and curative therapy.
• Pap test has proven effective in detecting precursor lesions which would have progressed to cancer if untreated.

CARCINOMA OF THE CERVIX

• Human papillomavirus (HPV): HPV infection is the most important risk factor.
• High risk HPV types for cervical carcinoma: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 and others
• Low risk HPV types for cervical carcinoma: 6, 11, 42, 44 (associated with condyloma) .
• Sexual activity: early age at first intercourse(coitarche), multiple sexual partners male partner with multiple prior sexual partners.
• oral contraceptives cigarette ,smoking, family history, associated genital infections, no circumcision in male partner

Diet

• Oral contraceptives
• immunosuppression.

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CARCINOMA OF THE CERVIX

• The normal cervix has a (narrow) transformation zone in which there is an abrupt transition from a columnar epithelium (sometimes via a metaplastic epithelium) to a squamous epithelium; HPVs are probably most infectious to cells that are close to this junction. The virus infects immature basal cells of the squamous epithelium.HPV viruses gain access to the basal epithelial cells of the cervix via the vagina (for example, during sexual intercourse.
• It can also access the basal epithelium in areas of breaks. The cervix is more vulnerable to HPV infection when compared to the vulva and vagina because it has large areas of immature epithelium.

CARCINOMA OF THE CERVIX

• After the HPV gains its entry into the basal cells, replicate episomally (outside the host chromosome in the nucleus) and express the (early) viral genes E1, E2, E4, E5, E6 and E7.
• The infected basal cells, which show signs of cell disruption as a result of the viral infection, continue their differentiation and migration to the epithelial surface, where the (now) squamous cells start to express the late HPV genes LI and L2. Infectious virus particles are formed and shed into the lumen of the vagina.

CARCINOMA OF THE CERVIX

• In transformed epithelial cells, HPV genes are integrated into the host chromosomes, with expression of (the oncogenic) E6 and E7 proteins, which bind to the tumour-suppressor proteins p53 and Rb

CARCINOMA OF THE CERVIX

• HOW DOES HPV ACT?
• HPV acts as a carcinogen using viral proteins E6 and E7 which interfere with the activity of tumour supressor proteins that regulates cell growth and survival
• Normal cells are arrested at the G1 phase but with HPV infection,cells (infected)continue to progress through the cell cycle.E7 protein bind the hypophosphorylated phase of retinoblastoma gene and promotes its degradation by the proteasome pathway.
• It also binds and inhibit the cyclin dependent kinases p21 and p27.
• E6 binds to P53 and promotes its degradation.

CARCINOMA OF THE CERVIX

• (HPV infection (particularly with the high-risk types) can progress to:
• (1) HPV-induced mild dysplasia,
• (2) the final stages of cervical intraepithelial neoplasia (CIN3) and, eventually,
• (3) invasive cervical cancer (CaCx), when the basement membrane is breached by the cells, allowing local spread and also distant metastasis. 20% of CIN3 eventually progress to invasive cancer.

CARCINOMA OF THE CERVIX

• DISEASE SPECTRUM.
• 1)HPV infection of immature basal squamous cells at the transformation zone. This is known as CERVICAL INTRAEPITHELIAL NEOPLASIA(low grade CIN at this stage).CIN1
• Virus multiplies episomally and accumulates in the cytoplasm as the cell gradually approaches the superficial layer. It also causes cell death.
• Huge numbers of the virus must accumulate in the cytoplasm before being visible as a KOILOCYTE.

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CARCINOMA OF THE CERVIX

• Viral DNA then integrates in the host cell genome. At this stage the lesion is a high grade CIN(2 and 3),viral copies do not accumulate in the cell and the koilocytes are absent.
• The viral proteins E6 and E7 take over the cells and they multiply incessantly till the cells eventually bridges the basement membrane and give rise to invasive cancer.

CARCINOMA OF THE CERVIX

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• PATHOLOGY
• Early stages of the cervical cancer are often poorly defined, granular, eroded lesions (endophytic)or nodular exophytic masses.
• Histologically, most tumours are non keratinising with solid nests of large malignant squamous cells. Others show nests of keratinised cells in concentric whorls, KERATIN PEARLS.

CARCINOMA OF THE CERVIX

• SPREAD
• Direct extension;
• Lymphatic spread
• Haematogenous route.
• Local extension into the parametrium results in compression of the ureters from which other complications arise such as hydroureters, hydronephrosis and renal failure

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CARCINOMA OF THE CERVIX

• Renal failure is the most common cause of death.
• Bladder and rectal involvement may lead to fistula formation.
• Lymph node metastasis also occurs.
• Distant metastasis can be to the liver, lungs and bone marrow.

CARCINOMA OF THE CERVIX

• Clinical features; post coital bleeding, bleeding after douching,foul smell.
• PREVENTION
• Pap smear remains an effective method of screening women for cervical cancer, it allows for early detection especially of the precursor lesions even before the patient come down with invasive cancers

ADENOCARCINOMAS OF THE CERVIX

• Constitute the second most common tumour of the cervix, it arises by the squamocolumnar junction and extends into the endocervical canal.
• Also associated with HPV infection :high risk types 16 and 18.
• Its precursor lesion is ADENOCARCINOMA –IN-SITU which is also known as cervical glandular intrepithelial neoplasia.
• Prognosis is however worse than squamous cell carcinoma.

UTERUS

• CONGENITAL ANOMALIES
• NORMAL MENSTRUAL CYCLE
• FUNCTIONAL ENDOMETRIAL DISORDERS.
• INFLAMMATORY CONDITIONS; Acute and chronic endometritis.
• OTHER BENIGN LESIONS; endometrioisis, adenomyosis.
• UTERINE TUMOURS
• ENDOMETRIAL TUMOURS(BENIGN,MALIGNANT)
• MYOMETRIAL TUMOURS(BENIGN,MALIGNANT)

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CONGENITAL ANOMALIES OF THE UTERUS

• A)Congenital absence of the uterus(agenesis):
• Failure of the mullerian ducts to develop. it is usually accompanied by other anomalies of the urogenital tract because elongation of the mullerian ducts in embryonic life requires the wolfian ducts as guides. there is also absence of the vagina and the fallopian tubes.
• B)Uterus Didelphys; refers to double uterus, due to failure of the two mullerian ducts to fuse in embryonic life. It is usually accompanied by double vagina.

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CONGENITAL ANOMALIES OF THE UTERUS

• C)Uterus duplex bicornis. A single uterus but with a common fused wall between two distinct endometrial cavities. Occurs due to failure of the common wall between the apposed mullerian ducts to degenerate and form a single cavity
• D)Uterus septus: single uterus with a partial septum due to incomplete resorption of the wall of the fused mullerian ducts.
• E) Bicornuate uterus: refers to a uterus with two horns and a common cervix

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NORMAL MENSTRUAL CYCLE

• The normal endometrium undergoes a series of sequential changes that support the growth of an implanted fertilised ova, if conception does not occur however, the endometrium is shed and regenerated in the next cycle.
• The endometrium under the influence of hormones from the hypothalamus, pituitary gland and the ovary undergoes these series of changes which are recognised histologically and are ‘dated” to clinically assess hormonal status, document ovulation and determine the causes of endometrial bleeding and infertility.

NORMAL MENSTRUAL CYCLE

• The endometrium in the menstrual cycle undergoes three phases which are
• Menstrual phase
• Proliferative phase
• Secretory phase.
• MENSTRUAL PHASE:
• In the absence of pregnancy, there is no blastocyst to secrete human chorionic gonadotrophin that stimulate the granulosa and theca cells (of the graafian follicle)to continue progesterone production, these cells degenerate and progesterone level falls. Endometrium breaks down, spiral arteries collapse and stroma disintegrates. Menses start on day 28 .

NORMAL MENSTRUAL CYCLE

• PROLIFERATIVE PHASE:
• This phase is marked by rapid growth of glands and stroma which arise from the basal layer.
• Early in this phase the gland are narrow and are lined by one layer of columnar cells but they gradually become coiled, they increase in caliber and are several layers (become pseudostratified)

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NORMAL MENSTRUAL CYCLE

• SECRETORY PHASE:
• Ovulation occurs on day 14 ,the graafian follicle releases the ovum and commence production of progesterone which transforms the endometrium from a proliferative to secretory state.
• Secretory activity is more prominent by the third week of the menstrual cycle. Glands enlarge ,dilate and become more coiled.

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NORMAL MENSTRUAL CYCLE

• Glandular cells develop abundant prominent glycogen rich subnuclear vacuoles by day 17.
• Stromal oedema occurs ,
• Stromal cells enlarge and exhibit abundant eosinophilic cytoplasm.
• Glycogen rich vacuoles move from the subnuclear to the supranuclear and secretion commences.
• With exhaustion of the theca and granulosa cells, progesterone level declines, the endometrium is prepared for commencement of the menses. If pregnancy occurs the endometrium moves from the secretory to the hypersecretory state.

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FUNCTIONAL ENDOMETRIAL DISORDERS

• Uterine bleeding can be a result of different diseases, the pathology can be traced within the uterus by several investigations.
• In some situations however, the cause of the bleeding cannot be found within the uterus. This is known as DYSFUNCTIONAL UTERINE BLEEDING(DUB).it is a clinical term for uterine bleeding not caused by any underlying structural(organic ) abnormalty.
• It occurs during or between periods.
• Most cases of DUB are related to a disturbance that involves the hypothalamic-pituitary- ovarian axis.

DYSFUNCTIONAL UTERINE BLEEDING(DUB

• The most common cause of DUB is anovulation.
• Anovulation is as a result of subtle hormonal inbalances and are commoner at menarche and perimenopausal period.
• Anovulation occurs when there is prolonged oestrogen stimulation without a post ovulatory rise in progesterone
• Endocrine disorders such as thyroid, adrenal or pituitary tumours
• Functioning ovarian tumours such as granulosa cell tumours
• Generalised metabolic disturbance such as marked obesity, severe malnutrition etc.

DYSFUNCTIONAL UTERINE BLEEDING(DUB

• Inadequate luteal phase is an ovulatory cause of DUB.It occurs due to indequate functioning of the corpus luteum resulting in low progesterone output and subsequent early menses .

OTHER CAUSES OF UTERINE BLEEDING

• Other causes of uterine bleeding or menstrual irreguarity which are intrinsic to the uterus are NOT considered dysfunctional, these include;
• Growths e.g carcinomas,endometrial intraepithelial neoplasia(EIN),submucosal leiomyoma,polyps
• Inflammation ;endometritis
• Pregnancy(complicated intrauterine or ectopic pregnancy.
• Intrauterine devices.

INFLAMMATORY CONDITIONS

• ACUTE ENDOMETRITIS
• Refers to abnormal presence of polymorphonuclear leucocytes in the endometrium. It is uncommon and limited to bacterial infections that arise after delivery or miscarriage. Retained products of conception are the usual predisposing factors. Common aetiological agents are group A haemolytic streptococci(Strept pyogenes),staphylococci etc.
• Curettage of the retained products and antibiotic therapy are employed in managing patients

INFLAMMATORY CONDITIONS

• CHRONIC ENDOMETRITIS
• Chronic endometritis occur in the following settings
• 1)in patients with chronic pelvic inflammatory disease.
• 2)in post partum or post abortion patients with retained products of conception.
• 3)in women with intrauterine contraceptive devices.
• 4)in women with tuberculosis either from miliary spread or from drainage of tuberculous salpingitis. This is however less commonly seen in recent times.
• Presence of plasma cells in the endometrium are diagnostic of chronic endometritis.

ENDOMETRIOSIS

• Endometriosis is the presence of endometrial tissue(endometrial glands and stroma) outside the uterus.It occurs in the following sites;
• Ovaries
• Uterine ligaments
• Rectovaginal septum
• Pelvic peritoneum
• Large bowel
• Small bowel
• Appendix
• Mucosa of the cervix
• Mucosa of the Vagina
• Mucosa of the Fallopian tubes.
• Laparotomy scars.
• umbilicus

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ENDOMETRIOSIS

• Endometriosis is a cause of infertility, dysmenorrhoea ,chronic pelvic pain. Several theories have been proposed to be the cause of endometriosis, these theories generally fall into two categories;
• Those that propose origin of endometriotic tissue from the uterus.
• Those that propose origin of tissue from cells outside the uterus that have the capacity to give rise to endometrial tissue

ENDOMETRIOSIS

• Common theories however include
• 1)benign metastasis theory: holds that endometrial tissue from the uterus can spread to distant sites like bone, lung, brain via the blood and lymphatic vessels.
• 2)metaplastic theory: endometriotic tissues arise from the coelomic epithelium same tissue from which the endometrial tissue arise.
• Extrauterine stem/progenitor cell theory; stem cell from the bone marrow can differentiate into endometrial tissue.

ENDOMETRIOSIS

• Patients present with severe dysmenorrhoea, dyspareunia, pelvic pain due to intrapelvic bleeding and periuterine adhesions, pain on defeacation (if it involves the rectal wall),dysuria (with bladder wall involvement).

Endometriotic lesions bleed periodically due to cyclic stimulation by the ovary or intrinsic ovarian stimulation.

The bleeding produces nodules, organising haemorrhages may be complicated by extensive fibrosis .Ovaries may be distorted by large cystic masses filled with brown fluid from previous haemorrhages;these are refered to as CHOCOLATE CYSTS or ENDOMETRIOMAS.

ADENOMYOSIS

• Presence of endometrial tissue within the uterine myometrium. Adenomyosis remains in continuity with endometriosis ,signifying downgrowth of endometrial tissue into and between the smooth muscle fascicles of the myometrium.
• Histology; irregular nests of endometrial stroma with or without glands are arranged within the myometrium separated from the stratum basalis by at least 2cm.

ENDOMETRIAL POLYP

• Endometrial polyps are exophytic masses of variable size that project into the endometrial cavity. Polyps may be single, may be multiple ;they are usually sessile but ocassionally may be large and pedunculated.
• Endometrial polyps may become hyperplastic in association with generalised endometrial hyperplasia. They are responsive to oestrogen but show little or no response to progesterone.

ENDOMETRIAL HYPERPLASIA

• It is defined as an increased proliferation of endometrial glands relative to the stroma, resulting in an increased glands to stroma ratio when compared with normal proliferative endometrium.
• Endometrial hyperplasia is an important cause of abnormal bleeding and a precursor to endometrial carcinoma. Both endometrial hyperplasia and endometrial adenocarcinoma involve inactivation of PTEN, a tumour suppressor gene.
• Endometrial hyperplasia is associated with prolonged oestrogen stimulation of the endometrium which may be due to anovulation, may also be due to increased oestrogen production from endogenous or exogenous sources .

ENDOMETRIAL HYPERPLASIA

• Other conditions associated with endometrial hyperplasia include;
• Obesity(involving periperal conversions of androgens to oestrogen).
• Menopause
• Polycystic ovarian syndrome
• Functioning granulosa cell tumours of the ovary.
• Prolonged administration of oestrogenic substances especially in oestrogen replacement therapy.

ENDOMETRIAL HYPERPLASIA

• Endometrial hyperplasia has been recently classified by the World Health Organisation into 2 major categories:
• Non atypical hyperplasia
• Atypical hyperplasia or Endometrial Intraepithelial Neoplasia.

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MALIGNANT TUMOUR OF THE ENDOMETRIUM

• ENDOMETRIAL CARCINOMA.
• Endometrial carcinoma is the most common invasive tumour of the female genital tract. It was initially far less common than cervical carcinoma but with increased awareness ,timely screening ,detection and intervention, incidence of cancer of the cervix has reduced.
• Endometrial carcinoma can be classified into two broad categories which differ in aetiology, age at presentation, genetic anomaly involved, behaviour etc

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ENDOMETRIAL CARCINOMA

• Type I (endometrial) carcinoma.
• Type II(serous) carcinoma.
• TYPE I ENDOMETRIOID CARCINOMA
• Type I endometrial carcinomas are the most common type.
• They are so called endometrioid carcinomas because they mimic proliferative endometrial glands.
• They are associated with obesity, diabetes, hypertension, infertility and unopposed oestrogen stimulation as they typically arise in the setting of endometrial hyperplasia.
• As with atypical endometrial hyperplasia, endometrioid carcinomas have been linked with mutation in the PTEN genes, other mutations also occur however.
• May be well differentiated, moderately or poorly differentiated.

ENDOMETRIAL CARCINOMA

• Type II (Serous tumours).
• Usually arise in the setting of endometrial atrophy, occurs in women who are 10 years older than those with type I carcinomas.
• There are three different subtypes; serous, clear cell and mixed mullerian tumours. Serous tumours are however the commonest subtypes.
• Mutations in p53 gene is the most common genetic anomaly, other mutations also occur

ENDOMETRIAL CARCINOMA

• Type II (contd)
• Patients usually present with irregular bleeding(in the younger women) or postmenopausal vaginal bleeding .Many patients however present late.

TUMOURS OF THE MYOMETRIUM

• LEIOMYOMAS.
• Syn.fibroids.
• It is the most common tumour in women.
• They are benign tumours of smooth muscle origin.
• May be multiple (may be single) whorled masses .
• They may be submucosal,intramural,pedunculated ,subserosal.

LEIOMYOMAS.�

• They are typically composed of bundles of smooth muscle cells, individual muscle cells have round to oval nuclei, long slender bipolar cytoplasmic processes.
• Many patients especially with submucosal fibroid usually present with bleeding, many intramural fibroids are asymptomatic.
• Large intramural fibroids may interfere with bowel or bladder function

FALLOPIAN TUBE

• The most common disorders affecting the fallopian tubes are infections, inflammation, ectopic pregnancy and endometriosis.
• Cysts:paratubal cysts and hydatids of morgagni are said to be remnants of the mullerian ducts and are said to be of little significance.
• Fallopian tube tumours are uncommon; recent data however suggest that serous cysts of the ovary arise from tubal neoplasms.

OVARY

• CYSTIC LESIONS
• POLYCYSTIC OVARIAN SYNDROME.
• OVARIAN TUMOURS

CYSTIC LESIONS

• Cysts are the most common cause of enlarged ovaries. A few arise from invaginated surface epithelium(simple serous cysts) while most others arise from ovarian follicles.
• Follicular cysts arise from unruptured graafian follicles or from follicles that have ruptured or immediately sealed. They are fluid filled structures lined internally by granulosa cells and externally by theca cells.

CYSTIC LESIONS

• Corpus luteum cysts result from delayed resolution of a corpus luteum’s central cavity. Menstrual irregularities may occur due to continued progesterone synthesis.
• A corpus luteum cyst is typically unilocular about 3-5cm in size .Cysts are lined by bright yellow tissue containing luteinised granulosa cells.

POLYCYSTIC OVARIAN SYNDROME

• SYN :Stein Leventhal syndrome.
• It is characterised by:
• Excess androgen secretion.**
• Menstrual irregularities.
• Polycystic ovaries(many small subcapsular cysts :12 or more)*
• Chronic anovulation**
• Decreased fertility.
• Hirsuitism
• Acne
• Male hair distribution

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POLYCYSTIC OVARIAN SYNDROME

• The main abnormalty is said to be increased androgen production by the ovaries and the adrenal glands as a result of abnormal regulation of the enzyme 17α hydroxylase which is active both in the ovary and the adrenal glands.

OVARIAN TUMOURS

• Ovarian tumours are numerous.
• Benign tumours are generally commoner among young women while the malignant tumours are commoner among the older women between 45 and 65 years of age.
• Most ovarian cancers have spread beyond the ovary at the time of diagnosis, they account for a disproportionate number of deaths from cancers of the female genital tract.

OVARIAN TUMOURS

• Ovarian tumours include:

1)Epithelial tumours; these arise from the serosal epithelium. They are divided into serous, mucinous, endometrioid, clear cell, seromucinous, brenner and undifferentiated tumours. All these are further sub classified as benign, borderline and malignant.

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OVARIAN TUMOURS

2) Mesenchymal tumours(stromal)

3)Mixed epithelial mesenchymal tumours.

4)Sex cord stromal tumours (arise from the stroma within the developing follicle).This is further subclassified as :

a)pure stromal tumours

b)pure sex cord tumours

c)mixed sex cord stromal tumours.

5)Germ cell tumours

OVARIAN TUMOURS

6)Germ cell-sex cord stromal tumours.

7)Miscellaneous tumours.

8)Mesothelial tumours

9)Soft tissue tumours.

10)Tumour like lesions.

11)Lymphomas and myeloid tumours

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OVARIAN TUMOURS

EPITHELIAL OVARIAN TUMOURS

SEROUS TUMOURS

SEROUS TUMOURS

• Are cystic neoplasms and include the most common malignant ovarian tumors.
• ‘serous’ describes the cystic fluid.
• Epithelium is similar to fallopian tube epithelium.
• Type I serous cancers are thought to arise from benign(endometriosis or cystadenoma) through borderline to low grade carcinomas.
• Type II serous cancers are high grade and said to arise from in-situ lesions from the fallopian tube or inclusion cysts from the ovary.

MUCINOUS TUMOURS

MUCINOUS TUMOURS

• They occur in mid adult life, rare before puberty and after menopause.
• Majority are benign and borderline.
• Benign tumours are composed of tall columnar cells with apical mucin ; they have no cilia.
• Borderline tumours show stratification and papillary growth.
• Malignant mucinous carcinomas demonstrate confluent growth.
• PSEUDOMXOMA PERITONEI: a condition with marked mucinous ascites, cystic epithelial implants, adhesions with frequent involvement of both ovaries.
• It may cause intestinal obstruction and death.

ENDOMETRIOID TUMOURS

ENDOMETRIOID TUMOURS

• These are characterised by the presence of tubular glands resembling benign or malignant epithelium as the case may be.
• Endometrial carcinomas may arise from endometrioisis, in some of these situations, areas of borderline tumours are seen(this describes the transition).
• Some endometrioid ovarian cancers occur at the same time as endometrial cancers, favorable outcome at the treatment suggests that both tumours occurred independent of one another rather than metastasis from one organ to the other.

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CLEAR CELL TUMOURS

• Benign and borderline clear cell tumors are very rare.
• Clear cell carcinomas are uncommon, occur in association with endometrial carcinomas of the ovary.
• Composed of large epithelial cells with abundant clear cytoplasm.

FIBROMAS,THECOMAS,FIBROTHECOMAS.

• Fibromas are ovarian stromal tumours composed of fibroblasts .
• Fibromas are unilateral in 90% of cases and are associated with MEIGS syndrome( ovarian fibroma, right sided hydrothorax and ascites).

Thecomas are composed of plump spindled cells with lipid droplets.

SEX CORD STROMAL TUMOURS

SEX CORD STROMAL TUMOURS

TERATOMAS

• They are the most common germ cell tumours.
• Most of them are benign.
• Composed of heterogenous collections of tissues from the three germ layers;
• Ectoderm: skin epithelium, sebaceous glands, hair follicles.
• Mesoderm; tooth, matured cartilage
• Endoderm: gastric glands

GESTATIONAL TROPHOBLASTIC DISEASES

• Gestational trophoblastic diseases are a spectrum of tumours and tumour like condition characterised by proliferation of placental tissue either villous or trophoblastic tissue. These include:
• Hydatidiform mole(complete or partial).
• Invasive mole
• Choriocarcinoma
• Placental site trophoblastic tumour

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HYDATIDIFORM MOLE

• Characterised histologically by cystic swelling of the chorionic villi with variable trophoblastic proliferation.
• They occur at the two extremes of reproductive life :in teenagers and in women between 40-50 years of age.
• They are usually diagnosed in early pregnancy, average of 9 weeks.
• Highest incidences are in the south east Asia.
• Women with a prior history of hydatidiform mole have a 20 fold greater risk of a subsequent molar pregnancy than the rest of the population
• Two types of benign non invasive mole;
• Complete or partial mole

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COMPLETE MOLE

• Results from an egg that has lost its female chromosomes, genetic material is completely(entirely)paternally derived.
• It is a placental with grossly swollen chorionic villi, resembling bunch of grapes which shows varying degrees of trophoblastic proliferation.
• A complete mole occurs as a result of fertilisation of an empty ovum that lacks functional maternal DNA.

COMPLETE MOLE

• Fertilisation may be ;
• Monospermic(one sperm) which is closely followed by duplication of the haploid set of chromosomes (23X which give rise to a 46XX mole).About 90% of complete moles are monospermic
• Dispermic involving two sperms fertilising an empty ovum(46XX or 46XY mole).10% of complete moles are dispermic.

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COMPLETE MOLE

• Women with complete mole usually present between 11^th and the 25^th weeks of pregnancy with excessive uterine enlargement(large for date ),bleeding with passage of small grapelike structures consisting of oedematous chorionic vili.
• Serum hCG(human chorionic gonadotrophin) are markedly elevated and continue to rise rapidly. There is a 2.5% of becoming choriocarcinoma and 10% of the lesion transforming into invasive mole
• Histologically, all chorionic villi are enlarged, scalloped in shape with central cavitations (cisterns). Trophoblastic proliferation which involves the entire circumference of the villi. Cytotrophoblast and syncytiotrophoblast

PARTIAL MOLE

• Results from fertilisation of an egg by two sperms. Karyotype is triploid 69XXY or tetraploid 92XXXY.
• It may also be by a single spermatozoon that failed in meiotic reduction. Fetus usually dies after 10 weeks of gestation and thus the mole is aborted shortly afterwards.
• Partial moles have increased risk of persistent molar disease but they almost never evolve into choriocarcinoma.

PARTIAL MOLE

• Histologically, there are two populations of chorionic villi. Only a fraction are enlarged and oedematous, the others appear normal. Trophoblastic hyperplasia is focal and less marked than in complete molar gestation.
• In partial mole, blood vessels are found within the chorionic villi and these contain fetal red blood cells.

INVASIVE MOLE

• This type of trophoblastic disease, the mole penetrate and may also perforate the uterine wall.Chorionic villi invades the myometrium.
• Tumour is locally destructive and may invade the parametrium.
• Tumour may also embolise to distant sites: lungs, brain but does not establish itself and grow like true metastasis, it eventually regresses even without chemotherapy.
• Women usually present with vaginal bleeding, abnormal uterine enlargement.
• Invasive moles are always associated with persistent HCG elevation

GESTATIONAL CHORIOCARCINOMA

• A rare malignant tumour of trophoblastic cells which may be derived from a previously normal pregnancy or even abnormal pregnancy like ectopic pregnancy.
• Non gestational choriocarcinoma may develop from germ cells in the ovary or the medastinum.
• Histology: proliferating syncytiotrophoblastic and cytotrophoblastic cells, abnormal mitoses amidst large areas of haemorrhages and necrosis.

GESTATIONAL CHORIOCARCINOMA

• Manifests as irregular vaginal spotting of bloody brown fluid. Some patients present with metastasis to the lungs, vagina, brain, liver, bone even the kidney.
• HCG levels are elevated.
• Treatment is by evacuation of the uterus with subsequent chemotherapy.
• Non gestational choriocarcinomas are resistant to chemotherapy.

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