causes of female infertility

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Q.1. what are the usual causes of female subfertility?

The usual causes of female subfertility are 1) Anovulation (mostly PCOS); 2 Minimal endometriosis 3) Tubal block 4) Pelvic adhesive disease 6) Myomas. . A) Delayed marriage 2) Delayed  Deferring the pregnancy-have se job security, own flat 3) Couples stays  employed in separate places and meet occasionally, 5) Infrequent coitus, excess stress and anxiety. Timing of coitus is important. Multiple times sex is needed to achieve pregnancy around the time OD ovulation. (Conception window-fertile window period of menstruation.)Promiscuity and more polygamy and rising prevalence of STI is one cause of concern. Smoking, environmental pollution, addictions, Life style changes are important modifiable factors which lead to subfertility. Delayed child bearing, rising prevalence of metabolic diseases, particularly PCOS and allied anovulatory disease, Endometriosis, Pelvic adhesive diseases, environmental pollutants causing damage to oocytes and presence of endocrine disruptors causing defective cell signaling. In order of prevalence the following are the common causes of female subfertility: - Anovulation (PCOS), Early endometriosis, Unexplained infertility.  Ovarian insufficiency and Immunological infertility is an uncommon cause.

Q.2-. Tests for medical fitness of pregnancy: - List of clinical & Lab tests so as to assess fitness of pregnancy? The following Lab tests are essential prior to pregnancy planning:- urine tests (RE & Culture and sensitivity test), Hb%, PP blood sugar, immune status Rubella & hepatitis, Vaccination against chicken pox, HIV, cervical Pap smear,

History of Female Partner: _History of any recent or past major illness?  Age of female partner is very important parameter. Duration of marriage? .Menstrual history? – Progressive dysmenorrhoea, Post coital acheà Endometriosis, Menorrhagia—Fibroids, Hypothyroidism; PID is an important cause of subfertility in Indian perspective. Delayed periods, Hypomenorrhoea, if no withdrawal bleeding then think of uterine synechiae, If FSH is high then POF or ovarian Insuffiency may be considered.

  PCOS Intraovarian modulation of androgen biosynthesis. Ovarian changes pertaining to Aromatase enzymes. Autocrine, paracrine and hormonal factors modulate the coordination of thecal and granulose cell function, in terms of androgen biosynthesis. Equal conc. of Androstenedione and T is contributed by adrenal & ovaries. So rise of T or androgens may be due to abnormal functioning of either ovaries or adrenals (Z. fasciculate) or both. In fact both the glands secrete Androstenedione in greater amount than T.  In fact 50% of circulating T is from peripheral conversion of the Androstenedione. The enzymes involved in conversion of cholesterol to AudioNet ARE SAM IN BOTH THE GLANDS. The rate limiting step in androgen formation is the gene expression of P450_c17, which (gene expression) is dependent on tropic hormones e.g. LH in case of ovary and ACTH in case of Adrenals.

Control of steroidogenic response is controlled by many growth factors, particularly-insulin and insulin –like growth factors (IGF) and other array of growth factors.

Androgen  formed in theca cells under the influence of LH à diffuse to granulose cellsà converted to E2 at granulose cells. As LH stimulation increases the homologous desensitization occurs. Overstimulation with LH in a time & dose dependent manner, cause DOWN REGULATION OF LH RECEPTORS à resulting in reduced rate of cholesterol side chain cleavage activity-> Both 17-20 –lease and 17 hydroxylase activity are decreased . As a result of reduced side chain cleavage the ratio of 17-OH P to androgen increases. Androgens and oestrogens are negative are negative modulators of LH effects. But IGF play a positive modulator role on the effects in production of androgen biosynthesis in the gonads.

ABC of Female Subfertility.

Female subfertility.

Primary amenorrhoea:

 - A) with normal sec sex charactersà Not responding to Oestrogen-progesterone Tryà Rokitansky syndrome/ Vaginal atresia. But if vaginal canal is presentà sec sex characters are absent/ even if the breasts are present à if uterus responds to withdrawal bleeds then either mosaic/ classical Turners syndrome. Hypothalamic diseases and Kochs infections of any organs of female body may predispose to genital Kochs.

Examine:--Nutrition, Anemia, active Kochs, Overweight, obesity, heart, liver, spleen, Lungs,

 c) Q3, what special advice as preliminary advices you like to impart? To maintain a diary of menstrual cycle and to have relationship during the middle part of cycle. Usually egg is released 12 days proceeding the first day of period. So record of three successive cycles will impart one when egg, in her case is going to be released? Husband, should, if stays outside the employed outside the state or inside the state but come occasionally must be informed as soon as periods ensue to make that month fertile.

List of investigations of female partner when she come for treatment?-

 Sion Test: Sonography particularly at the middle part of menstrual cycle – will yield much information’s- uterus-any abnormality, tumours, endometrial development as per day of cycle, any ovarian cysts etc. Size of follicle upcoming egg will help. SIS: - Sono Salpingography: - to demonstrate uterine cavity and tubal patency; SIS or saline Salpingography is a better diagnostic help then traditional HSG. SIS or saline Salpingography is a better diagnostic help then traditional HSG. Screening for reproductive tract infections: -- Syphilis, Chlamydia, - Kochs, Hepatitis serology, HIV, Gonorrhea, Serum progesterone on day 21 of menstrual cycle .or Urinary LH kit.

Asymptomatic- next step after two years of marriage will be Hystero-Salpingography-to test the patency of fallopian tubes. HSG: - Tubal patency. Post coital Tests: - If more than 7 motile sperms are seen in high power microscopy 12 hrs after coitus then one can presume that the seminal parameters are near normal and she is possibly normal- couple gets convinced that all is possibly well and no major abnormality is there.

Symptomatic--Overweight, irregular periods, Acne, family history of DM, Stressful life, Employed ladies: - investigate hormones particularly thyroid, Prolactin, day 3 or day 4 of cycle LH, Metabolic Parameters:  Serum PP insulin, PP Sugar.

Laparoscopy. It diagnoses the endometriosis and tubal diseases. Lateral end of fallopian tube must be in very close approximation of ovaries so that ovum is sucked inside the fimbria end of fallopian tube by negative pressure and not that ovum escapes, and the rolls over to tube. So, a good Tubo-peritoneal relationship is essential. Free movement of tube without any pelvic adhesion is an essential part for conception. List of investigations of female partner when she come for treatment?-

 Sonography particularly at the middle part of menstrual cycle – will yield much information’s- uterus-any abnormality, tumours, endometrial development as per day of cycle, any ovarian cysts etc. Size of follicle upcoming egg will help. Serum progesterone on day 21 of menstrual cycle .or Urinary LH kit.

Asymptomatic- next step after two years of marriage will be Hystero-Salpingography-to test the patency of fallopian tubes. Symptomatic-  Overweight, irregular periods, Acne, family history of DM, Stressful life Serum progesterone on day 21 of menstrual  cycle .or Urinary LH kit.

Asymptomatic- next step after two years of marriage will be Hystero-Salpingography-to trust the patency of fallopian tubes. Symtomatic-Overwight, irregular periods, Acne, family history of DM, Stressful life, and Employed ladies: - investigate hormones particularly thyroid, Prolactin, day 3 or day r4f cycle LH, Serum PP insulin, PP Sugar

Q12. What are the usual treatments that are offered in case of female subfertility?

General:- Obesity-Weight reduction, Lifestyle changes-Yoga, relaxation exercises, morning walk, going to cinema .Theatre/ club with husband, Enjoying holidays (week end); Endorphins will help so also serotonin and allied hormones will help. The level of bad hormones like cortisol, adrenaline, nor adrenaline will, hopefully become less so

 To avail fertile days.  How frequent the intercourse be suggested?- Once in 2-3 days during the period span of 10-20 days-of 28-30 day of cycle. But long abstinence is bad as it will produce bad quality and dead sperm. Abstinence is one of the common causes of IUI/ IVF failure. All myths regarding the intercourse should be counselled-posture, position, timing, washing, douching etc.

Treatment of female factor. Drugs: - as required. Ovulatory Drugs. Ovulation induction. This is a common method of treatment of subfertity. The principle is either to a) directly administer gonadotrophins b) to administer agents which will indirectly stimulate gonadotrophin productions e.g. by selective oestogen receptor modulators --- oestrogen modulators- (CC which is SERM & those agents which decrease production of oestrogens locally inside the ovary—Inhibitors of oestrogen synthesis.)  c) To improve the local factors and control intraovarian enzymes and ovarian millieu. The role of local factors in the development of follicles is immense. Oestrogen modulators are of two types :- 1) modifying of aromatase inhibitors à thereby minimizing oestrogen production inside the ovary.

CC: - when there is failure of ovulation in spite of six cycles of CC then it is called CC Resistance. But if there is no pregnancy despite documented ovulation then it os called CC failure.

 Why at all CC fails? The common causes are 1) Insulin resistance 2) Who Type 1 Anovulatory disease –diseases of Pituitary /hypothalamic disease- where serum oestrogen is low. WHO 3 type of anovulatory disorders –Medical diseases which prevent ovulation like- Thyroid, CAH, and hyperprolactinaemia.

What are the causes of  clomiphene Failure i.e. no pregnancy despite ovulation?- Associated pelvic diseases like endometriosis, PID, Myomas, Pelvic adhesive diseases,& most importantly undiagnosed tubal factors and endometrial receptivity factors and obviously male factors. Additionally many such women if tubal factor and male factors are not further evaluated but switched over to AI/Gonadotrophins àif preg ensues then we can substantiate that CC associated anti-oestrogenic action may be responsible.

History of Ovarian stimulation:-

1958:---Pit. Gonadotrophins= Gemzell= & coworkers had first noticed that ovarian stimulation was possible in humans: 1958 extracted=Later human preg achieved in 1961.

1961:- Greenblatt and his coworkers discovered CC called product MRL/41): JAMA: 1961: 178101-14. Does it cause increased incidence of cong. Heart diseases amongst fetuses born of CC.

Insulin sensitizer:-

Aromatase Inhibitors-Inhibitors of oestogen synthesis.-2000—Mitwally MFM & Casper RF.

What are the adjuvant drugs that can be used in conjunction with CC?- Such agents are 1) INSULIN SENSITIZERS 2) Bromocriptine  3)Gonadotropins with or without agonist down regulation/ antagonist   4)  oestrogens  5) Sildenafil & Ecosprin  6)  Top up LH and or hCG 7) Dexamethasone  - 8)  9) Growth hormones  10) Anti-oxidants. 11) Pretreatment with OCP-

How does pre-treatment with OCP acts?-a) Less amount of gonadotrophin is needed—especially if Stimulation is initiated 5 days after one can overlap agonist and OCP but that should be less than 5 days, preferably 1-2 days.   b)     c) It reduces the formation of ovarian cysts during agonist thereby allows programming the cycle with reduced interval of low oestogen prior to stimulation.

How does pre-treatment with only oestrogen acts?-

In many centers before CC/AI are prescribed it is customary to prescribe 4 mg of oestradiol valerate in previous cycle midluteal phase. From Day 21 of previous cycle; à after discontinuation of oral E period commences/ or start stimulation on the discontinuation of E. (see p. 143) of Rizk. By administering E2 prior to initiation of stimulationà by that resting follicles have uniform size and not heterogeneity of folliclesà and pre-treatment with E2 increases sensitivity to stimulation. This is an important step in OI particularly in poor responders. Additionally synchrony of the cohort of follicles capable of responding to FSH.

 Adjunct therapy in ovulation induction (Contd)How does pre-treatment with Dexamethasone Acts/ Helps? :-   A) either administer 0.5 mg continuously b ) some use higher dose of Dexamethasone  of 2 mg OD but only during the 5 days of stimulation and 5 days after / following stimulation. Some use 1 mg. The ratio of cortisol/ cortisone in follicular fluid has been strongly correlated with IVF successà and it has been reported that administering 1 mg OD through the cycle à administration of glucocorticosteroids improve the health of oocytesà even in IVF cyclesà If the women is not obese then it is better than metformin as an adjunct therapy.

How minitreatment with HCG does help?

The place of LDA in OI protocol?

The place of Bromocriptine in OI protocol?

The place of Growth Hormones in OI protocol?

The place of DHEA/ Testosterone patch in OI protocol?

Agonist down regulation can in fact increase the rate of OHSS (though it prevents Pre LH surge in 100% of cases and increased formation of residual cysts.

Tubal Block: - Is it due to Tubectomy, particularly laparoscopic? Then, better plan for Lap repairs by competent hands, after release the ova is capable for fertilization for 6-8 hrs only. Later become uunfertilizable. In ordinary cases there is no place for daily sonography or Cx mucus study. Neither there is a necessity of BBT.

Stratification of cases:-Patient selection and categorization of subfertile couples are important.

 First to identify the cause as far as possible. Counselling, express the expected outcome. But public expectation is high. There is increased professional responsibility.

No standard Step wise investigation have been framed till date due to variety of women coming with different age group with many associated medical disorders. Stratification at appropriate centers is essentials.

Q. What are the complications of Ovulation Induction?

Multiple gestations

2) Ovarian hyperstimulation

Increased prevalence of congenital anomalies of foetus.-? Heart disease of foetus.

Increased prevalence of pregnancy loss: - Preclinical loss if serum Beta HCG is 25 IU/L; and clinical if a gestational sac was visible. In spontaneous pregnancies –the prevalence of spont ab was 20.4% and in cases of CC induced preg. --> This was 23.7%.There were more preclinical loss. ( 5.8% vs. 3.9% in spot) But if the women concerned is aged > 30 yrs than spont loss will be 3.7% and cc loss will be 3% only. Many confounding    factors play role in subfertile women. Advanced maternal age, presence of endometriosis and prevailing insulin resistance as occurs in PCOS are the other independent factors of causation of spont abortion.

UNEXPLAINED SUBFERTILITY.

Prevalence : Of all subfertile women about 5-10% cases no cause for subfertility is disclosed inspire of USG, SIS, PCT, Hormone assay, immunological Tests, Sperm function tests, Chromosome tests, X-ray, Laparohysteroscopy,.

In such cases it will be better for ICSI/IVF.

D & C is not usually done.

 agents, Insulin sensitizers, Dietary adjustments,

DHEASO4.

 

PCOS, Non-PCOS secondary amenorrhoea, all anovulation women, woman suffering from Galactorrhoea, acne, alopecia, hirsutism, Acanthosis nigricans , all obese women-warrant detailed endocrine evaluation to arrive at a definitive diagnosis. These seven groups of women and women heading for induction of ovulation and unexplained infertility mandate detailed but selective endocrine evaluation-though most cannot afford. An experienced astute clinician can select which hormone to test –and other endocrine test at a later date.

PCOS

PCOS is a syndrome and many diseases can mimic/present as PCOS. Fertile or not fertile -it is not sufficient to simply stamp a woman as PCOS. All PCOS are endocrinologically alike,

We have to find the exact endocrine abnormality in a given PCOS and select most suitable treatment for her. In fact adolescent PCOS also mandate diagnosis of exact endocrine disorder for the origin of PCOS and then select appropriate treatment protocol. In such adolescents- it is more due to cardio-metabolic aberration induced by “Adiponectin-Leptin-Ghrelin-insulin disorder “backed up tyrosine kinase activity disorders.

 In fact we formulate the treatment plan to treat a PCOS on the bases of her hormonal aberration which are not alike in all PCOS. Some exhibit high insulin or high androgen levels, some exhibit hyperprolactinaemia, high DHEASO4 or rarely cortisol. The clinician cannot ask for testing all the six hormones.

Phenotypic analysis helps us to select which hormones to test- test by exclusion.

Oligomenorrhea Similarly, in cases of oligomenorrheic there are many cause mostly endocrine disorder. If she does not want fertility is not an issue, diagnosis by exclusion O subfertile women may be due to following clinical conditions as well. And each disease mandate different treatment protocol for their primary disease and also for treatment of subfertility.

Hirsutism: Such clinical conditions which mimic PCOS (oligomenorrheic/ eumenorrheic) and with without hirsutism mandate endocrine evaluation to arrive at a definitive clinical diagnosis. Such condition are 1) NC-CAH (Nonclassic adrenal hyperplasia), 2) Cushing syndrome, 3) Virilizing ovarian tumour-all presenting with evidence of hyperandrogenism. The other four conditions which usually present as PCOS 4) hypothyroid, 5) hyperprolactinaemia, 6) acromegaly, and 7) premature ovarian failure (Oligomenorrhoea, weight gain, ovarian enlargement) are. Sometimes 8) drug-related hyperandrogenism may report to us. Elicit detailed drug history before much money is spent on hormone testing with an erroneous diagnosis of PCOS of endocrine disorder.

In cases of dysthyroidism both TSH and T4 measurements are essential.

Premature Ovarian Failure: - One should insist on endocrine confirmation.

Unnecessary hormone testing

It is true that selections of endocrine tests is guided by the personal and then present history. We often miss this and do unnecessary hormone testing like androgen levels and PRL, Cortisol, DHEASO4 in all cases of PCOS who do not need it.

Continuum of symptoms:    To whom to consider that it is classical PCOS? The problem is that all the four features of PCIOS are not present in all cases of PCOS and even if present do not express in equal severity. The problem is that symptoms appear as spectrum of symptoms and signs the occurrence which is dissimilar. It is a continuum and we have to add more endocrine tests as clinical signs appear. The usual sequence is Acne/slight hair growthàslight aberrations in M. cyclesàWt gainà

But if a girl was born in mother who had PCOS, hyperandrogenism, dyslipidaemia, & now that mother are diabetic then there is a resin to believe that this adolescent girl is suffering from adolescent Classical PCOS.A low birth weight, premature puberache (appearance of pubic hairs before the age of 8 years.)-need much vigilance for onward development of PCOS. Puberache is an expression of premature activation of Hypothalamus-Pituitary-Adrenal axis.

The issue of Hyperprolactinaemia.

If two fold raise that will speak of hyperprolactinaemia. In 20-40% of clinically diagnosed PCOS PRL will be slightly raised but to diagnose that PRL is the primary cause of PCOS (no other endocrine disorder) - then there should be at least two fold rise of PRL. This is due to hypooestrinismà activation of Lactotrophà more release of PRLà mastodynia, tenderness of breasts and bloating. If less than double level-do not treat by dopamine agonist. Better treat by Insulin sensitizers if unmarried and by OCP if married and does not seek for restoration of fertility Role of estimating 17 hydroxyl progesterone.

This is a screening test for CAH (adult onset type) which is also called as NCAH-non classic Adrenal Hyperplasia.

 The sample should be drawn in early follicular phase and the result should be normally

Stress and Female Subfertility...

Causes of elevated DHEASO4 1) attenuated adrenal enzyme deficiency- proved by ACTH stimulation test; 2) Cushing syndrome & Adrenal Tumours are uncommon causes of raised DHEASO4,

In cases of documented NC-CAH & also in cases where there has been repeated anovulation inspire of CC- then administration of dexamethasone will increase the adrenal pool of androgens.

In some cases it will improve the ovulation rate. 

But after one month of initiation of dexa- morning cortisol should be done to assess the degree of suppression of endogenous cortisol by exogenous Dexa. If cortisol is< 3 mcg. /mlàthen the dose of Dexa should be decreased. It is not used in pregnancy, Decapeptyl. 1 × 2 plus rec Hcg. Double trigger -- Decapeptyl. 1 × 2 plus rec HCG - -

 It can be used in Antag cycle with high BMI & more prone for OHS & it also decrease

 If you have a good freezing back up, then go ahead with agonist surge in an antagonist cycle in all hyper responders and freeze all the embryos. You will have 100% ohss free cycles. If you are weak in the Cory program, then do the double trigger and complete by a fresh transfer, but still with a chance for late ohss.