WORKSHOP PENATALAKSANAAN INFERTILITAS

TATA LAKSANA
FAKTOR UTERUS

Sri Ratna Dwiningsih

Staf Divisi Fertilitas Endokrinologi Reproduksi
FK Unair-RSUD Dr. Soetomo
2023
HUMAN REPRODUCTION PROCESS:

1. Sperm must be deposited at or near the time of ovulation, ascend into

fallopian tubes, and have the capacity to fertilized the oocytes (male factor)
2. Ovulation of a mature oocyte must occur, ideally on a regular and predictable
basis (ovarian factor)
3. The fallopian tubes must capture ovulated ova and effectively transport sperm
and embryo (tuba factor)
4. The uterus must receptive to embryo implantation and capable of supporting
subsequent normal growth and development (uterine factor)
Uterine Infertility Factor (UFI)

The mayor causes of infertility:

• Ovulatory disfunction (20-40%)
• Tubal dan peritoneal pathology
(30-40%)
• Male factors (30-40%)
• Uterine factor : uncommon
• Unexplained infertility
Uterus
Cervical mucus:
• accepts sperm from the
ejaculate,
• excludes the seminal plasma Estrogen
Post Not
and morphologically
abnormal sperm
coital test recomendation
• Abnormality of cervical
• nurtures sperm mucus production is rarely
biochemically, • Cervicitis, stenosis cervix
• serves as a reservoir can be identified by
inspeculo
• The result not change
clinical management (IUI
and IVF)
 Uterine factor infertility

Anatomi abnormality Functional abnormality

• congenital malformations, • chronic endometritis
• leiomyomas, • abnormalities of
• intrauterine adhesions, endometrial
• endometrial polyps receptivity
Anatomi abnormality
Uterine factor infertility: congenital malformations
• Prevalence: 2-4% (0.3%) (2%)

(0.5%) (1.1%) (3%)

• Septate uterus is the anomaly most highly associated with reproductive failure and obstetrical
complications.
• The risk of spontaneous abortion was significantly increased in women with septate (RR, 2.81),
bicornuate (RR, 2.40), and unicornuate (RR, 2.10) uteri
Diagnosis:
Three basic methods for evaluation of the uterine cavity: HSG, TVUS or saline
sonohysterography, and hysteroscopy.

Management:
• Hysteroscopic resection of a uterine septum was shown to lower the risk of
miscarriage (RR 0.37, 95% CI 0.25– 0.55) compared to untreated women with
septate uteri.
• Surgical intervention for incidentally discovered uterine septa without a history
of infertility or miscarriage is controversial.
• Surgical intervention for bicornuate uteri or uterine didelphys is not
recommended
Suggested management algorithm for
options to acquire motherhood in women
with absolute uterine factor infertility
(agenesis uterine)
 Uterine factor infertility: Leiomyomas

Mechanism infertility relating to myomas:

• Displacement of the cervix, decreasing exposure to sperm
• Enlargement or deformity of the uterine cavity, interfering
with sperm transport
• Obstruction of the interstitial segment of the fallopian
tubes
• Distorted adnexal anatomy, interfering with ovum capture
• Distortion of the uterine cavity or increased or abnormal
myome trial contractions, inhibiting sperm or embryo
transport
• Impaired uterine blood flow, chronic endometritis, or
decreased endometrial receptivity, interfering with
implantation
 Uterine factor infertility: Leiomyomas

Myoma uteri size - infertility

• Submucosal myoma uteri has negatively affect fertility
• Intra mural fibroids above a certain size (>4 cm), even without cavity distorsion,
may also has negatively influence fertility
Best Prac Res Clin Obstet Gynaecol. 2016 Jul;34:66-73

• Intramural fibroids of size >4 cm were seen to be associated with statistical

lower pregnancy rates in comparison to smaller intra mural fibroids. The effect
of size could thus be seen in combination with the fibroids location
EMJ Repro Health. 2019/5 (1):94-99
 Uterine factor infertility: Leiomyomas

• Myomektomi laparoskopi dapat dilakukan untuk pemulihan yang lebih cepat

setelah operasi (Rekomendasi A)
• Miomektomi laparoskopi dapat dilakukan bagi wanita yang menginginkan
kehamilan (Rekomendasi A)
Konsensus HIFERI : Myoma uteri, 2021

Decisions regarding the management of infertile women with asymptomatic

intramural myomas are among the most difficult clinical judgments.
They must consider not only the size, number, and location of myomas and the
risks and benefits of the procedure but also age, duration of infertility, ovarian
reserve, other infertility factors.
Speroff, 2020
 Uterine factor infertility: Intra uterine adhesion
• 90% of cases, intrauterine adhesions relate to curettage for pregnancy
complications
• Intrauterine adhesions can be asymptomatic or cause menstrual disorders
(hypomenorrhea, amenorrhea, dysmenorrhea), pain, recurrent miscarriage, or
infertility.
• Diagnosis: Hysteroscopy (Gold standart)
• Treatment: adhesiolisis by hysteroscopy
• Vaginal administration of misoprostol (200–400 μg) for cervical softening before operative
hysteroscopy
• Various physical barriers, including both unmedicated intrauterine device (IUDs) and balloon
catheters, to maintain separation between the opposing layers of the endometrium during the
immediate postoperative interval
• Postoperative treatment with exogenous estrogens to promote rapid reepithelialization and reduce
risks of recurrent adhesions is frequently used, but its efficacy has not been established
 Uterine factor infertility: Intra uterine adhesion

• Adesi intrauterin yang terjadi akibat endometritis tuberkulosis (TB) dapat diobati dengan
regimen pengobatan yang sama dengan TB Paru.
• Terapi Rifampisin, Isoniazid, Pirazinamid, dan Etambutol atau RHZE diberikan selama 2
bulan dilanjutkan terapi RH selama 4 bulan pada endometritis TB.
• Laju kehamilan spontan post terapi anti tuberkulosis berkisar 31-50%
• Operasi pada endometritis TB tidak lebih efektif dibandingkan dengan terapi menggunakan
rifampisin dan obat lainnya, selain itu komplikasi seperti peritonitis dan perdarahan dapat
terjadi pasca operasi.
• Prognosis fertilitas pada endometritis TB bergantung pada tingkat keparahan, namun pasien
dengan adesi yang parah memiliki prognosis yang buruk.
• Prognosis fertilitas yang baik didapatkan pada pasien yang mendapatkan pengobatan TB
lebih awal. (level of Evidence IV) → Rekomendasi C

Konsensus HIFERI, 2019: Penanganan infertilitas

 Uterine factor infertility: endometrial polyps

• Prevalence of 15.6% among women with unexplained infertility, ranged between 1.4 and 8%
among women undergoing ART.

• Saline sonohysterography is the most useful method of imaging for detection of endometrial
polyps,
• Infertile women with documented but unresected endometrial polyps (<2 cm), IVF outcomes in treated
(preliminary hysteroscopic polypectomy) and untreated women were not different.

• Polypectomy may improve reproductive performance in infertile women.

• Treatment must be individualized, depending on the size of a polyp, associated symptoms, and
circumstances leading to its discovery
 Functional abnormality
Uterine factor infertility: chronic endometritis
• Chronic endometritis (CE) is inflammation in the endometrial lining characterized by plasma cell
infiltrate that has been associated with both recurrent implantation failure and pregnancy loss.
• 57–66% of women with unexplained infertility or unexplained recurrent implantation failure are
diagnosed with chronic endometritis

• Chronic endometritis may be diagnosed at the time of hysteroscopy based on direct observation :
mucosal edema, focal or diffuse endometrial hyperemia, or the presence of micropolyps.

• Mucopurulent cervicitis is highly associated with chlamydia (Chlamydia trachomatis) and

mycoplasma (Mycoplasma genitalium) infection, and both organisms, in turn, are associated with
chronic endometritis

• Empiric antimicrobial therapy may resolve chronic endometritis on repeat endometrial biopsy and
small studies suggest an improvement in live birth rate
Uterine factor infertility: abnormalities of endometrial receptivity

The window of endometrial receptivity is restricted to days 16–22 of a 28-day normal cycle (5–
10 days after the LH surge) and days 16–19 of cycles stimulated by exogenous gonadotropins

The maximal chance of a normal implantation is only about 40% per cycle under optimal
conditions
 Uterine factor infertility: abnormalities of endometrial receptivity

Endometrial receptivity is heralded by the progesterone-induced formation of

pinopodes (also called uterodomes), surface epithelial cells that lose their microvilli
and develop smooth protrusions, appearing and regressing during the window of
receptivity
Factors that disturb receptivity :
• endocrine causes,
• inflammatory events,
• thin endometria,
• abnormality anatomy of uterine (fibroids, polyps, septa)
• immunologically mediated disturbances.
 Uterine factor infertility: abnormalities of endometrial receptivity
The rule Progesteron at implantation:
• Progesterone modulates maternal immune responses (protection of the
semiallogenic fetus),
• improves utero-placental circulation and vasodilatation,
• decreases apoptosis,
• promotes extravillous trophoblast invasion in the maternal decidua,
• remodeling the local vasculature,
• suppresses the fetal immuno-placental inflammatory response,
• decreases uterine contractions, and induces cervix ripening
• Upregulatd Keratinocyte growth factor (KGF). When progesterone and KGF2
levels drop, the blood supply of the endometrium and muscle layers decreases
• Progesterone protects ovarian function against ischemic reperfusion injury
through antiapoptotic and antioxidative propertie
 Uterine factor infertility: abnormalities of endometrial receptivity

Methods for assessing endometrial receptivity:

• transvaginal ultrasound imaging (TVUS),

• histologic evaluation by endometrial biopsy,
• endometrial receptivity array (ERA),
• ReceptivaDx test (BCL6)
 Uterine factor infertility: abnormalities of endometrial receptivity

Methods for assessing endometrial receptivity:

Transvaginal ultrasound imaging (TVUS)

• TVUS is a widely available tool that can be used to assess endometrial
receptivity.
• TVUS can be used to measure the endometrial thickness, volume, and pattern.
• A recent meta-analysis found that endometrial thickness >7mm, endometrial
volume >2mL, and trilaminar pattern had 99%, 93%, and 87% respective
sensitivity for assessing endometrial receptivity.
 Uterine factor infertility: abnormalities of endometrial receptivity

Methods for assessing endometrial receptivity:

Histologic evaluation by endometrial biopsy

• The histologic sampling does not provide an accurate or reliable assessment of

endometrial receptivity and is not currently used to assess endometrial
receptivity in clinical practice
 Uterine factor infertility: abnormalities of endometrial receptivity

Methods for assessing endometrial receptivity :

Endometrial receptivity array (ERA)
• The ERA is a molecular diagnostic tool used to identify a receptive endometrium via a specific
transcriptomic signature present in both natural and hormone replacement therapy cycles.

• This is done by taking an endometrial biopsy at specific times during the mid-luteal phase (LH
surge+7 days in natural cycles, progesterone starts +5 days in hormone replacement/”artificial”
cycles)

• The results of the ERA are then used to guide shifts in the timing of progesterone
administration before embryo transfer in a future cycle.

• Most data evaluating ERA-timed embryo transfers and associated pregnancy rates have failed
to see an improvement in the live birth rate in these cycles
 Uterine factor infertility: abnormalities of endometrial receptivity

Methods for assessing endometrial receptivity :

ReceptivaDx test (BCL6)
• The ReceptivaDx test identifies endometrial receptivity defects associated with
progesterone resistance.

• The BCL6 protein is overexpressed in women with endometriosis

• BCL6 protein overexpression is associated with lower clinical pregnancy rates in

women undergoing IVF

• its ability to improve IVF outcomes is still undergoing investigation

 Uterine factor infertility: abnormalities of endometrial receptivity

Treatment abnormality of endometrial receptivity

• Full understanding, psychological support and empathy;

• Natural progesterone in a case of insufficient luteal phase (200 mg orally or

vaginally at bedtime from day 14-25th day

• Estroprogestogens for women with ovarian insufficiency (premature ovarian

failure, early menopause, etc.)

• Dopamine agonists for hyperprolactinemia

 Uterine factor infertility: abnormalities of endometrial receptivity

Treatment abnormality of endometrial receptivity

• Prednisolone 10-20 mg/day: may prevent recycling in the circulation of cardiolipin or suspend
the discharge of embryo-toxic factors or factors associated with HLA; lowers NK (CD
56+/CD16+) cells.

• Aspirin 100 mg should be given preconceptionally. It may suspend cyclooxygenase action on

platelets by suspending the composition of thromboxane thrombosis and thus preventing
vascular thrombosis in placental blood vessels.

• Heparin: heparin of low molecular weight prevents chorionic villous sampling phospholipids
from being destroyed by assisting in the successful implantation in the early stages of
pregnancy.
 Uterine factor infertility: abnormalities of endometrial receptivity

Treatment abnormality of endometrial receptivity

• Ca: 500 mg, vitamin D 1000 mg

• Metformin: decreases androgens, improves endometrial function and

implantation, decreases IR; glycodelin and IGF-1 protein expression is
corrected.

• Folic acid: 0.5-2 mg for normalizing homocysteine level

• L-arginine, L-carnitine, acetyl-L-carnitine, N-acetylcysteine

 Uterine factor infertility: abnormalities of endometrial receptivity

Treatment abnormality of endometrial receptivity

• Melatonin 2 mg at bedtime

• Anxiolytics in low doses

• Sildenafil, a selective inhibitor of 5-phosphodiesterase, an enzyme included

in cGMP hydrolization, decreases NK cell activity. Vaginal suppositories 25
mg every 6 hours is suggested in the proliferative phase

• Intralipid 20% intravenously (9 mg/ml total blood volume) cor- responds to 2.

ml of intralipid 20% diluted in 250 mg saline
 RINGKASAN
1. Uterine factor is uncommon caused infertility
2. Uterine factor infertility caused by: anatomy abnormality and functional
abnormality
3. Anatomy abnormality of the uterus diagnosed by HSG, TVUS, and Histeroscopy
4. Treatment anatomy abnormality of the uterus can be performed: surgery,
surrogacy, uterus transplantation, adoption
5. Treatment functional abnormality of the uterus can be performed by
medicamentosa, depends on the causal.
THANK YOU