Spermatogensis -its hormonal control

Hormonal control of spermatogensis.

Hormone nature of origin function molecule

1 GnRH(LHRH) It is Decapeptide in nature, Source is Hypothalamus Acts on pituitary gland to secrete FSH and LH.

2 FSH : nature:---Glycoprotein : Source is pituitary gland Acts on Sertoli cells. Sertoli cells produce inhibin and also initiates spermatogenesis.

3 LH is Glycoprotein in nature, Source is pituitary gland :: Stimulated Leydig cells, which produce testosterone and maintain spermatogenesis

4 Prolactin Nature is Polypeptide Source is Pituitary (adenohypophysis) Mode of action:- Accentuates the LH effect on Leydig cells.

5 Testosterone : Chemical nature is steroid : source is Leydig cells : Effect is :maintenance of spermatogenesis. it also acts as a prohormone for estriol (E-2) and dihydrotestosterone.

6 Estrogen Chemical nature is steroid extraglandular: Source is : . Fat , Liver and muscle tissue

by aromatization of testosterone and

androstendione. Mode of action:-- regulation of LH secretion.

7 inhibin : source is from Sertoli cells : Function: is inhibition of pituitary FSH secretion and it is also a Glycoprotein in nature.

8 activin is from Leydig cells Chemical nature is Glycoprotein acts on simulation of pituitary FSH secretion

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Abnormal Hair Growth of hairs u in women

Hirsutism (Androgen Excess Syndrome)

Hirsutism is defined as presence of excessive amount of coarse hair of male distribution seen in a female, causing unacceptable cosmetic concern. Such areas include face, chest, abdomen, thighs and back, etc. A semi-quantitative analysis of hirsutism can be made according to Ferriman D and Gallway JD Nine body areas of hormone sensitivity for hair growth are graded from 1 to 4 (minimal hair to frank virilization) and ultimately the grades in each of these areas are summed together. If the score is more that 8 it indicates hirsutism. The amount of hair growth differs among various ethnic and genetic groups. It is much decreased in Orientals, for example the Chinese and increased in Mediterranean’s. Hirsutism must not be confused with virilization. Hirsutism does not always signify major pathology or serious endocrine disturbance. In several hirsute women the disturbance is due to excessive activity of  5 alpha reductase in the skin. The enzyme releases dihydrotestosterone (DHT) from testosterone carried along with sex hormone binding globulin (SHBG). Hirsutism may also occur due to excessive sensitivity of hair follicles to DHT. This kind of sensitivity is known as constitutional Hirsutism of no serious pathological significance except that it is unacceptable to the patient. But hirsutism can also be the earliest sign of a serious disorder like an androgen producing tumor. Hirsutism of recent organ must be viewed with suspicion particularly if the degree of hirsutism is increasing with time. This is due to androgen levels increasing in the system caused probably by neoplasm. Frank virilization characterized by clitoromegaly deepening of voice and alopecia may all follow this kind of hirsutism.

Androgen excess syndrome can occur due to several causes. Sixty to eighty percent of these women are said to be having PCO syndrome. The syndrome is seen in 5 percent of general population of reproductive age group. They may not all be infertile nor will they all be hirsute. Forty to sixty percent of them are obese 50 to 90 percent are oligomenorrheic and 50 to 70 percent of them may have hirsutism of low or high order. The high level of androgens and cyclical estrogen production causes disruption of HT-HP gonadal axis resulting in elevated LH-FSH ratio. Many women with PCO have metabolic disturbances some showing insulin resistance and compensatory hyperinsulinemia with or without abnormal glucose tolerance (GT). Some of the women with PCOS have dyslipidemia caused both by high levels of insulin and androgens. Hirsutism caused by hyperinsulinemia may show at least a partial response to administration of insulin sensitizing agents like metformin.

HAIR –AN Syndrome: This syndrome connotes a group of symptoms, which include hyperandrogenism, insulin resistance and acanthosis nigricans. In this syndrome, the predominant feature is hyperinsulinemia due to insulin resistance. The mitogenic action of insulin on the basal cells of epididymis causes a velvety hyperpigmented patches or streaks in skin creases. Although PCOS is also along with HAIR-AN syndrome the degree of metabolic disturbance seen in HAIR-AN syndrome can be of a much higher order.

Congenital Adrenal Hyperplasia(CAH) is a disorder caused by deficiency of 21 hydroxylase enzyme

Cushing syndrome: The clinical presentation of this syndrome is primarily that of abnormal fat deposition of the body, thinning of skin with striae, glucose intolerance, osteoporosis, muscle weakness along with all the other signs of PCO syndrome.

Androgenic tumors: Androgens producing tumors of ovary or adrenal gland can cause hirsutism. But they are rare. This should be suspected when the onset of symptoms are sudden and the progression is rapid. Hormone producing tumors are usually of low malignancy. When signs of excessive secretions of cortisol are present associated with virilization one must look for adrenal tumors or secondary androgenism caused by  PCO syndrome, etc. Unlike PCO or Cushingoid pathology, virilising  ovarian tumors exhibit the form of sudden onset of hyper-androgenism with frank virilization. These include Sertoli-Leydig cells and lipoid cell tumors.

Endometrial Receptivity & Implanation failur in IVF

Hostile endometrium is a common cause of implantation   failure.. How do we assess Endometrial Receptivity in IVF??

Embryo transfer (ET) forms  the ultimate procedure in the program of ART. The person who does the ET must have adequate information regarding the dimension of uterus, the length of cervical canal; difficulty in negotiating the internal OS and the angle between the cervical canal and body of the uterus. All these should have been recorded after a preliminary hysteroscopy during which one would also exclude other disturbing features like the presence of synechiae, small myoma, adenomatous polyps, foreign bodies and large areas of bald endometrium etc.

  The sonologist must report on collection of fluid in the uterine cavity during the course of stimulation protocol; if such a thing is reported, the fluid has to be aspirated and sent for bacteriological examination either by culture or by PCR examination for inflammatory conditions caused by Chlamydia and tuberculosis. Chronically infected tubes might swell up during stimulation protocol forming a hydrosalpinx and such fluid might be propelled into uterine cavity by increasing peristalsis stimulated by elevated estrogen levels. Mucoid fluid usually suggests chronic infection of genital tract.

  Thickness of endometrium is a very important feature to reckon with for the success of ET. An endometrial thickness of less than 7mm on the day of HCG is most unlikely to produce a pregnancy. It must be appreciated that in a natural uniovular cycle of a woman, the Serum  E2 at the time of ovulation is around 250 pg/ml and the endometrial thickness may be anywhere between 8 and 14 mm. On the other hand in a cycle of controlled ovarian hyperstimulation (COH) the S,E2 level may rise up to anywhere between 1000 and 3000 pg/ml at the time of HCG administration; but one frequently gets disappointed to see that the endometrium does not necessarily grow in parallel with the increasing Serum E2 level. The causes of endometrial growth lag may be many. Chronic infections like tuberculosis can produce destruction of basal endometrium because of which the endometrium may never grow to optimal thickness. Exogenous estrogen administered orally or intramuscular may not reach the endometrium at all. It may be taken up by the liver, metabolized and eliminated before it reaches the uterus. On suppositories reach the endometrium directly by diffusion, thus increasing the endometrial thickness and receptivity without increasing the level of these hormones in the serum.

  Quite frequently Doppler blood flow velocity study of endometrium is seen to be at a very low level without any demonstrable cause. The absence of a multi-layered endometrium associated with uterine artery pulsatility index (PI) of more than 3 at the time of HCG injection is an ominous sign. The absence of sub-endometrial blood flow should give a warning regarding endometrial vascularisation and increase implantation. But, such an observation has not been supported by most of the workers. When both endometrial thickness and vascularity are subnormal, it is wise to postpone ET to a cold cycle for a frozen embryo transfer (FET). The cause of endometrial deficiency has to be evaluated and any therapeutic measures available shuld be instituted. A good protocol for hormone replacement therapy may be substituted.

  Hyper-echogenic endometrium on the day of administration of HCG may be a contraindication for ET. Highly echogenic endometrium appears white. During the follicular phase of menstrual cycle endometrium appears dark between the endometrium lining the myometrium and that lining the endometrial cavity. During luteal phase of the endometrium, echogenicity increases giving a whitish, smudgy appearance. This kind of change may be seen as early as the fourth day of P exposure.

Hyperinsulinaemia and PCO

What is HAIR-AN Syndrome, polycystic Ovary and its relation to Infertility??

High circulating insulin concentration has been noted in some forms of PCO. The association of hyper-androgenism, extreme insulin resistance and acanthosis nigricans (HAIR-AN syndrome) is recognized as one extreme end of the spectrum of PCOS. These patients show signs of ovarian hypertrophy with hirsutism, clitoromegaly and elevated androgen levels. Many such individuals show extreme obesity. But some workers have shown hyperinsulinemia in 30 percent of lean PCOS patients and 65 to 70 percent of obese patients.

  It is not known whether the defect in glucose metabolism causing hyperinsulinemia is congenital or acquired. The popular belief is that it is gene-related because several families are identified where, majority of siblings in the family are affected. In order to achieve a euglycemic state, there will be a rebound activity of islet cells of pancreas leading to hyperinsulinemia.

 While some PCO women show an uncompensated picture of hyperglycemia along with hyperinsulinemia (non-insulin dependent diabetes) most women show euglycemia with hyperinsulinemia. There are some women who are even hypoglycemic due to overcompensation. Such women with untreated hyperinsulinemia can eventually go to pancreatic failure and insulin deficiency diabetes.

Mechanism of hyperinsulinemia may be due to several factors. It may be due to increased pancreatic sensitivity to hyperglycemia, decreased hepatic clearance of insulin and peripheral target tissue resistance. The last is probably the most accepted hypothesis. The resistance may be caused by three possibilities. In type A syndrome, hyperinsulinemia is due to decrease in number of insulin receptors in target tissue due to mutation of insulin receptor gene. In type B syndrome, hyperisulinemia is due to autoantibodies to insulin recetors. In type c syndrome, which is the largest group of hyperinsulinemia, it is due to post receptor defect caused by interference with signal transduction.

 The relationship between insulin and insulin-like growth factor I (IGF-1) and ovaries

Receptor for insulin and IGF-I have been demonstrated in human ovaries. Both hormones have a mitogenic effect on granulose cells in culture. They augment the ovarian steroidogenic capacity in vivo by potentiating the effects of gonadotropins. They stimulate FSH induced estradiol (E2) and progesterone (P) synthesis in granulose cells and LH induced androstenedione (A) and testosterone (T) synthesis in theca and stromal cells. The serum concentration of testosterone decreases when serum insulin level is reduced. Insulin receptors have been demonstrated in pituitary. The increase in LH: FSH ratio in PCOS is partly attributed to increase in LH hormone production by pituitary due to the effect on insulin.

  Normally under physiological circumstances, insulin does not play any important role in steroid production in ovary. IGF-1 is the molecule active at physiological concentrations, which helps in regulation of ovarian function in vivo. Insulin and IGF-1 receptors share many structural and functional properties allowing a certain degree of cross-reactions at supraphysiological concentrations.

  Increased insulin is said to module the production of sex hormone binding globulin (SHBG) in the liver. There is a strong negative correlation between rising levels of insulin and falling levels of SHBG produced by liver. Increase in SHBG reduces free testosterone level. Likewise fall in SHBG (which occurs) in hyperinsulinemia can result in increase in free testosterone level and this appears to be the most important factor that determines the feature of hirsutism in PCO women.

Follicular Development and Insulin: Insulin may disrupt normal folliculogenesis:

1   insulin can act as a mitogenic factor and can stimulate other growth factors like IGF-I and IGF-II which can affect ovarian follicular development and cause multiple ovarian cysts and ovarian enlargement.

2   Insulin can interfere with orderly function of gonadotropins by releasing LH out of turn. It has been shown that at the time of puberty, young girl show evidence of insulin resistance and hyperinsulinemia at a time when they produce multiple cysts in the ovaries. Hyperinsulinemia, multicystic ovary (MCO) and onset of menarche seem to be intimately connected. Multicystic ovaries resolve in course of time. On occasions, the MCO can persist and may later on take the appearance of PCO. It has been found that circulating insulin levels are directly proportional to ovartian volume in both PCOS and women with multi follicular ovaries (MFO) thus promoting the hypothesis that insulin contributes to genesis of both PCO and MFO.

Therapy in PCO:  the goal of thereapy in women with PCOS  is to

·    Reduce serum androgen levels- particularly important in women seeking treatment for hirsutism

·    Improve ovulatory function and regulate menses-of importance in infertile women enhance weight loo-important in obese PCOS.

·    Halt metabolic disturbance that follow hyperinsulinemia, such as glucose intolerance, dyslipidemia, hypertension and atherosclerosis in elderly women.

·    To prevent onset of complication due to unopposed action of estrogen like endometrial hyperplasis, carcinoma of the breast etc.

Treatment of hyperinsulinemia seems to reduce most of the adverse effects of PCOS. But treatment of hyperinsulinemia can only be an adjuvant to other types of therapy immediately required to alleviate the patients’s problems of infertility.

Combined Oral contraceptives-Health risks

Some scientists are of opinion that low dose COCs containing gestodene or desogestrel might have  a lower risk of AMI How does oral contraceptives affect adversely the cardiovascular system (The COC  and circulatory diseases)??

Q.1: Which circulatory  diseases  have been shown to be  more common in COC users ?
1) Systemic hypertension : this is  not so much  a disease  in its own right  as it predisposes to and does its damage through  the arterial  circulatory  diseases. However clinician should aver preset mind before such COC is prescribed for women with hypertension. Arterial diseases  include Myocardial  infarct, Thrombotic  strokes  
Haemorrhagic   strokes and others  arterial events such as  mesenteric  or retinal arteries which are very rarely seen in COC users. Synthetic oestrogens   have been  shown to raise  arterial blood pressure  both in short  term challenge experiments   and in longer  term studies. That is why natural oestrogens containg pills have been available as COC which does not promote arterial  thrombosis, venous thrombosis, not to speak arterial hypertension. In  the majority  of combined pill users there is a  slight  measurable    increase in both systolic and diastolic blood pressure   within   the normotensive  range.   Early large  studies showed a 1.5-3  times higher   relative risk of  clinical hypertension . Modern  varieties  with reduced  biological   impact  of the   oestrogen and progesterone   have reduced such risk  but not eliminated   this risk. However    the new progestogen drospirenone in  combination  with EE as  Yasmin led in one premarketing study  to a very  small but significant   fall in mean  blood pressure. Whether   this will translate   into greater   safety  of that  formulation for arterial disease especially  when  there are risk factors  remains  for further   study and reports. Increasing the  dose of progestogen leads to an increased rate   of diagnosis  of clinical   hypertension .When    oestrogen   was kept constant the incidence  of arterial   diseases both  as a group and individually was correlated with the progestogen dose . Predisposing  factors include strong family history   and a tendency  to water  retention and obesity  Past pregnancy  associated hypertension   does not predispose  to hypertension   during OC  use in  controlled  studies But  the RCGP  study showed  that past  toxemia  history     does predispose to myocardial   infarction  especially  in smokers .Hypertension   is an important  risk factor for the arterial  diseases to be considered  in detail below especially heart  disease  and  both types  of stroke. 
As of 2003  what do we really know  about how the COC affects  the various  cardiovascular   diseases?
CARDIOVASCULAR   DISEASE AND  STEROID  HORMONE  CONTRACEPTIVES 
On 3-7  November   1997  WHO  convened in Geneva a Scientific Group  Meeting  on Cardiovascular Disease    and Steroid  Hormone  Contraception  Acknowledging  the major  changes that have taken  place in the hormonal  content   of combined   oral contraceptives  and  prescribing   patterns the Scientific   Group   pain particular   attention to studies that included  data collected after 1980 . The Scientific  Group  concluded  that the incidence  and mortality rates of all cardiovascular   diseases  in women of reproductive age  are very  low. Any additional cardiovascular    disease    incidence   or mortality   attributable  to oral  contraceptives is very small  if the users do not smoke    and do not have   other cardiovascular risk factors.  The background papers   prepared   for the meeting  have been published  in the journal  Contraception   

  
.   Take home message :-there is  increasing  evidence  that no formulation of COC is  atherogenic   unless there is first an arterial   risk factor  such  as  smoking .When such arterial   risk factors are present   however  it remains a tenable hypothesis that these apparently lipid  friendly products  might reduce  arterial disease risk   relative  to other   products 




2) COC induced Venous  disease like, Deep venous  thrombosis .Pulmonary embolism, rarely  thrombosis in important single veins  e. g  mesenteric  hepatic or retinal . Current  users of COCs  have a low    absolute  risk of VTE  which is  none   the less 3-6  times that  in non users. The risk  is probably highest  in the first year of use and declines thereafter    but persists  until discontinuation .After use  of COCs is discontinued  the risk of venous thrombo embolism drops  rapidly to that in non users .Among  users of COC  preparations containing  less than 50 ug of ethinylestradiol the risk of venous    thrombo embolism   is not related  to the dose   of oestrogen. 
COCS containing desogestrel    or gestodene   probably carry  a small risk   of VTE  beyond that  attributable   to COCs containing  levonorgestrel …There  are insufficient data to draw  conclusions  with regard  to COCs containing  Norgestimate. 
The absolute   risks of VTE attributable to use of  oral  contraceptives  rise with increasing age obesity recent   surgery  and some  forms of thrombophilia. Cigarette  smoking  and raised  blood  pressure  which are  important   risk factors  for arterial  disease do not appear  to elevate the risk of  venous  thrombo embolic  disease .There are  insufficient  data  to conclude   whether there is a relation between VTE   and the use of  progestogen  only contraceptives  . The  relative  risks of venous  thrombo embolic  disease  observed  in users of combined oral contraceptives  in developed  countries  appear  to be applicable  to developing  countries
Q.3: Why and How CC cause such thrombogenic tendency?? Can any of these risks be explained by known metabolic  changes induced by the artificial  hormones  of the  COC? In particular what is the influence of the oestrogen  content in the causation of  arterial / venous thrombosis ? 
Ans:.  Alternations in clotting factor levels   induced by oestrogen   might be thrombogenic.  More important   changes include   reduced levels of   anti thrombin III and protein  S  but there  are also  increased   levels of fibrinogen and several of the vitamin K dependent  coagulation factors . These changes help  to explain the increased  risk of venous thrombosis  particularly  if the woman already has congenital   or  acquired  predisposition  such as factor V Leiden and antiphospholipid  antibodies  .However    it is likely that if there is already significant  arterial  wall disease oestrogen  might also promote  superimposed  arterial    thrombosis . COCs alter  the plasma  concentrations of many  components  of both  the coagulation   and fibrinolytic  systems . These  changes  are les marked  with COCs  containing   low doses of  ethinylestradiol and even less so with progestogen only contraceptives  Hereditary conditions     such as  anti thrombin  III  defect    and factor V   Leiden   mutation predispose    women to  venous thrombo embolism . These   disorders might underlie a large  proportion of idiopathic  venous  thromboembolic  events perhaps   one third   of those   seen in Caucasian  women  . this effect  is increased  in women using  COCs, 
The  prevalence   of hereditary  conditions  such  as anti thrombin  defect  and factor  V  Leiden mutation is about   5% in Caucasian  women but is lower in other populations. The    positive  predictive  value of   screening  for these disorders is very low. 

Q.4: But in clinical practice we don’t see quite often the arterial or venous thrombosis. What is your explanation in this regard??  Ans: Surprisingly, there is evidence of a compensatory increased fibrinolytic activity   which is also an   oestogen effect.    This   might in part explain the rarity of overt disease especially   arterial disease in non smoking   pill users. 
Q. 5: What may be the altered metabolic profile after administration of oestrogens??  Ans: A series of biochemical changes are possible after administration of oestrogens.  Fortunately some are counteracted by Progesterone administration simultaneously. For instance, hepatic secretion of many different proteins is stimulated   by oestrogens . Such    proteins are involved in the transport of hormones, vitamins and minerals and thereby indirectly  control   blood pressure  and immunological  processes . As mentioned earlier, when oestrogen is given the stimulatory effect can sometimes be suppressed by concomitant administration of a progestogen.   But the interactions are complex there might  also be synergism or independence of the effects and differences  between  progestagens.  
Q.6: What may be advantage of progesterone??  Ans: The  risk of venous thrombo embolism which     still seems to be primarily caused by oestrogen  might be modified  by progestogens  in some   way as  yet to be fully  explained 

Q7: What about HDL?? Many   studies  have shown  that if a constant dose  of  oestrogen  is given  then  the oestrogen   induced  high density lipoprotein cholesterol  increase  is reversed  by LNG . . 
Q. 8: Does COC promote Acute  myocardial infarction?? 
Data   are available   which   show that increasing age, cigarette smoking,   diabetes, hypertension   and raised  total  bold cholesterol  are important  risk factors  for AMI   in young  women. The scientific Group  concluded  that  the  incidence   of fatal  ad non fatal  AMI is very low  in women of  reproductive age . As such women who do not smoke ,   who have their   blood pressure   checked  and who do not have hypertension   or diabetes   are at no increased risk  of AMI  if they use  COCs when compared  with never users  of the same age. There  is no increase  in the risk of AMI with increasing  duration of use  of COCs Thee is no increase  in the  relative risk of AMI  in past users  of COCs too. But women    with hypertension   have  an increased  absolute   risk of  AMI  . The  relative   risk of AMI in current users in of COCs  with hypertension is at least three times that in current users without hypertension. 
What about smokers?? The increased absolute risk of AMI  in women  who smoke  is greatly elevated   by use of COCs especially  in heavy smokers  . The relative   risk of AMI in heavy smokers  who use COCs might be as high   as 10 times   than   in non smokers  who use  COCs .Given  the relevance  of smoking  as a serious   risk people   take for granted  it is salutary  to not that the 1985  report   of the RCGP  showed  that the pill  user who  also smoked  was not only more likely  consequence -  a higher   case fatality rate  was noted  in smokers. 

What about aged women and use of COC?? Although   the incidence of AMI increases exponentially with age  the relative  risk of AMI  in current  users of COCs does not change  with increasing  age. The available  data  do not  allow the effect  of the dose  of oestogen on the relative   risk of AMI  to be evaluated independently  of the type  and dose of progestogen. The incidence of fatal  and non fatal  ischaemic  stroke  is very low in  women of reproductive  age but  increases with increasing age 

Q.10 What about dose of oestrogens and CVS risks?? Some scientists are of opinion that low dose COCs containing gestodene or desogestrel might have  a lower risk of AMI.  There are insufficient   data to assess whether the risk of AMI in users of low dose COCs is modified by the type of progestogen. The suggestion that users of low dose COCs containing gestodene or desogestrel might have  a lower risk of AMI than users of low dose formulations  containing     levonorgestrel  remains  to be substantiated 
The  above   conclusions  appear  to apply equally to women in  developed and developing countries. 
Ischaemic  stroke 
The  scientific  Group   concluded that 
The reported  estimates of relatives risk of ischaemic  stroke   associated  with use of combined  oral contraceptives  have decreased  since the  earliest  epidemiological   studies  linking use  of oral contraceptives   with stroke. 
What about ischaemic stroke with pills ?? Are nonsmokers are absolutely safe??  Ans:-In women   who do not  smoke who have   their blood pressure   checked  and who do not have hypertension the risk of ischaemic stroke  is  increased  about   1.5 fold  in current users   of low dose   combined oral  contraceptives compared with non  users. There  is no further   increase  in the risk of ischaemic  stroke  with increasing  duration of use of  COCs.  Women  who have  stopped  taking COC are at  no greater  risk of ischaemic  stroke than women who have  never  used oral contraceptives. About women with hypertension have  an increased absolute risk of ischaemic stroke . The relative risk of ischaemic  stroke in current  users of COCs with hypertension appears to be at least  three times   that in current   users without   hypertension. 
The   absolute  risk of ischaemic stroke  in women  who smoke  is about   1.5-2 times    that in non smokers this  risk is multiplied by a factor of  2-3  if such women are   current  users of COCs .The risk   of ischaemic stroke  in users  of COCs   containing  high  doses if oestrogen is higher   than that  in users of COCs containing  low doses of oestrogen. There     are insufficient data  to allow any conduction to be drawn  about whether the risk of ischaemic  stroke  is related to the type  or dose  of progestogen contained in low dose  COCs .These conclusions appear  to apply equally in developed and developing  countries. The incidence of fatal and non fatal haemorrhagic stroke is very low in women of reproductive age in both developed and developing countries  .
What is the take home message on ischaemic stroke?   In women aged less than 35 years  who do not  smoke and who do not have hypertension  the relative  risk of haemorrhagic   stroke associated   with use   of COCs  is not increased. There is no increase in  the risk of haemorrhagic   stroke  with increasing duration of use of  oral  contraceptives. Women  who have  previously  used  oral contraceptives  are at no greater risk   of haemorrhagic  stroke than   women who   have  never used  them. 
What about haemorrhagic stroke??  Ans: Women  with hypertension have an  increased     absolute risk of haemorrhagic stroke. The relative risk  of hemorrhagic    stroke  in  current    users of COCs  with hypertension might  be 10 times that   in current   users of COCs  with hypertension  might be to times that in current users without   hypertension. The risk   of haemorrhagic    stroke in women who   smoke is up to twice  that in non   smokers  in women   who are current  users of COCs and who smoke the relative  risk is about  3 times than age matched. The incidence   of hemorrhagic  stroke  increases  with age  and current    use of COCs  appears  to magnify this effect   of ageing .There is no evidence     that either  the oestrogen   or the progestogen  constituent of   COCs  is related  to the risk   of haemorrhagic   stroke. 
Possible  biological mechanisms  for cardiovascular effects  
. COCs affect lipoprotein and carbohydrate metabolism haemostasis and mechanisms regulating    blood pressure.  An  influences  on the functioning  of the endothelium   of blood  vessels   and arterial    tone also  seems likely The Scientific   Group   suggested  that the potential   significance of these  changes  should be investigated  and interpreted  using new models  of vascular   pathophysiology  the scientific Group   concluded   that .The biological    mechanisms underlying cardiovascular   disease   involve  a complex   interplay between lipoprotein   metabolism   humoral regulators  such as    insulin coagulation  and fibrinolysis the rennin   angiotensin  aldosterone system  and the functioning   of the  endothelium of blood vessels. 

Does COC cause Diabetes?? Ans: COCs do not increase the risk  of developing  diabetes   mellitus . They have little  effect on fasting plasma  concentrations  of glucose   and insulin but cause  modest  elevations  in the plasma  levels of glucose  and insulin after an oral  glucose  challenge  and might increase   insulin  resistance.  The clinical   significance of such changes in otherwise   healthy young   women is unknown   especially  in relation to arterial  disease. 
What about COC & the changes in metabolism of lipoproteins  in plasma  ??    Ans:  changes  in metabolism  of lipoproteins  in plasma  induced by  uses of COCs have  been extensively  studied  low dose  COCs  increase  fasting plasma    levels  of triglycerides but have  only minor   effects  on low density   lipoproteins lipoprotein   or total  cholesterol. The effect on HDL depends   on the balance of oestrogen  and progestogen the clinical    significance    of such changes   is uncertain  in the content of current   low dose  formulations .
Even low dose COCs  cause  modest elevations in blood    pressure that might   increase the risk of arterial disease . In healthy young  women with a low   background   risk of arterial  disease  small  increases   in blood pressure  attributable  to use of COC are likely  to have   minimal  effects on the absolute   risk of arterial  disease. 
Comparative   studies  of users of low dose COCs suggest  that the done  and type of the progestogen   component    influence   the effect  of these preparations on lipid   and lipoprotein   metabolism  and haemostasis  . The   clinical  significance  of these  differences   is uncertain. 
 Recommendations for further   research 
The scientific  Group   made a number  of recommendations regarding  areas of future   research  related  to the risk of  cardiovascular    disease and the use of steroid contraception – interested readers  are referred  to the  last edition of this book  or to WHO  Technical Report  857 .
Making informed  choices about  COCs 
Any  assessment  of the risk of  cardiovascular   disuse associated  with COCs is complex,. Nevertheless it is  clear that  mortality  rates   from cardiovascular disease  are extremely  low among  women of reproductive age and that  the added risk of using  steroid  contraceptives  is also very  low Within the  context of the everyday  risks  of modern life steroid   contraceptives are safe. Factors  that need to be taken  into account when determining  a woman ‘s  risk of cardiovascular   disuse while  using COCs  include. 
The age specific  incidence  of each cardiovascular  condition 
The strength of the association    between  use of COCs  and each cardiovascular   outcome the  woman’s  age and presence  of other risk  factors  for cardiovascular  disuse such  as smoking  and a history     of hypertension . Whether there are important differences  in risk between  particular  formulations of COC and if so the choice  of formulation.The number  of cardiovascular  events attributable  to the  use of COCs is very  small especially   among users of all ages who do not smoke   and among younger users  who smoke. The number   of associated  deaths   is even smaller  and again  is highly dependent   on whether   the user is a considered against the very  high contraceptive efficacy  of COCs  and the rapid   reversibility of this effect after they  are stopped. The use of  less reliable  alternative   methods of contraception    exposes  women to an increased risk of pregnancy a  condition  that is associated  with a higher    incidence  of venous  thromboembolic   disuse than that associated   with the use of any of the  currently available low dose COCs  In addition  COCs  are associated with   many non contraceptive  benefits  including  a reduced  risk of endometrial   and ovarian cancer. By any standard all of the  currently available  low dose COCs can be   regarded   as safe 
The study Group concluded  that 
Any  increase  in incidence  of or mortality from cardiovascular disease  attributable to use of COC is very  small if users do not  smoke  and do not have   other risk factors     for cardiovascular  disease  . for example among  users   of COCs who do not    have risk   factors  for  cardiovascular   disease   the annual risk of death attributable    to use of  oral contraceptives is approximately   2 deaths   per million users at   20-24  years of age , 2-5  per million users  at 30-34  years   of age and  
The risk   of mortality  from cardiovascular    disease  attributable to use of  oral contraception   is much  greater    among women  aged 40-44  than  among women aged  20-24  years  
At  any given  age a woman who  smokes   but who  does not use oral contraceptives  is at greater  risk of death from arterial disease than a user of oral contraceptives who does  not smoke. 
The benefits of blood  pressure  measurement  in reducing  the risk of  cardiovascular   disease attributable to use of  oral contraception  increase with the age of the user. 
Venous   thrombo embolic  disease  is the most  common  cardiovascular  event among    users of oral contraceptives However it contributes very little  to any increase in the number  of deaths since the associated   mortality    is relatively  low compared  with that associated  with arterial  diseases. Long term disability from non fatal  venous  thrombo embolic disease  is also low. 
What is the difference between   relative risk and  absolute  or attributable  risk? 
This is   most important   distinction which  is not often  understood  by either patients  or journalists notably in relation to venous  thrombo embolism Twice   almost   nothing out  of a million is still almost  nothing Pill takers  can  relate to the analogy  that being   given  a  second lottery   ticket does not  make you    hugely more likely  to win even  though  doubling   your chances. 
A small relative  risk   might easily cause  more attributable  cases    than a large   one if the background prevalence   is high and vice  versa 
The  frequency  of hepatic cellular   adenoma  in controls as compared   with COC  users using older  50 ug plus pills. The second set come from Table 5.8 which  itself is from the 1998  report of the WHO’s  special Scientific Group  They apply to smokers aged 40-44 who would have an increase in relative risk of acute myocardial infarction of only 1.5  if they additionally took  the modern low dose pills at that age but the attributable  number of  extra cases   is 85 per million Contrast only 19 extra cases  of hematoma   in the first  set of figures   despite a 20 fold greater   relative risk. 
Neither statistics is good news . but  the difference in the excess number of cases caused explains   why it was  reasonable to  accept   for 50 ug plus pills a 20   fold increase  in the risk of   benign liver   tumours . however    a mere 50 %  increase  in AMI  through  more modern  pills is widely considered  unacceptable  for smokers  above age 40  
Dr Pal , shall we refund the COC  which we have purchased  after promulgation of Lock Down and purchase condom in lieu of that ? What is your honest unbiased advice?? Adv: Life  is pretty risky   believe  it or not each  year one  has a  1:1000   chance  of  having  to visit   a Casualty Department  through  a home  injury   from a bottle  or a can . The risk  of dying through  pill taking   is less than   one hundredth  of the risk  of death through   smoking  20  cigarettes  a day  for example..      Potential users  can be reminded  that there are  many other  risks in life excluding COVID-19. And Pill induced VTE, Myocardial.  However   intelligent and educated  couple (most  of our patients / relatives  who seek advice over phone  ) are amazingly  risk illiterate on medical aspect  . Contraceptive seekers (they are not Patients )   are naturally anxious  about the known  adverse  effects  of the combined pill on cancer   and circulatory   disease . Assuming they otherwise wish to use the method   how can   this anxiety be reduced? 
The  media  / regional magazines  do the general  public  a disservice by tending to exaggerate the bad systemic  effects  and by not pointing  out the counterbalancing non  contraceptive benefits aside from the advantages  of efficacy   reversibility and convenience .Many risks are far greater than pill taking yet cause minimal  concern for  example  having babies  or travelling by car – let alone smoking .For those who are not very numerate risks  are best   expressed in relative  terms . At least   three  deaths  have been reported   at the Brampton  hospital  through  allergy  to hamsters. Finally prospective pill  takers can be reminded  that the tiny risks of the COC   can be further   reduced by careful  prescribing  of lower  dose preparations  with good  subsequent  monitoring  

What is Clomiphen citrate failure/ Clomipfene citrate resiatnce??

What do we mean by CC resistance??

What are the causes of CC failure?

Ans: CC failure (documented ovulation ether by LH kit or by Folliculometry) / resistance (anovulation) have many causes which should be assessed before embarking on another Ovulogens- be it oral/ parental. 

Scrutiny of all previous records is a must : What was the indication of CC therapy earlier ??  Ans: PCOS of several phenotypes is the usual indication which often lead to either anovulation or oligo ovulation or poor oocyte quality due to androgen excess (letrozole acts here to reduce intraovarian hyperandrogenism). Metformin if administerd as an adjunct hopefully will decrees hyper insulinaemiac and decrees serum IGF 2 and thereby facilitate quality oocyte by maintaing normal endocrine milieu intraovarian .However sufficient time should be offered to  scrutinized the luteal phased length (LPD) and to cheek the previous monitored cycle (any evidence of thin endometrium –cc induced) & , dose of cc employed. Any adjunct used or not??  

Etiology of persistent anovulation (CC resistance / CC failure) taken together  inspite of 150mg CC (maximum total 2-4 cycles ).  Ans: Maximum 3-4 cycles should be tried, depending on age  and not exceeding 4 cycles Causes CC failure are possibility of host of anatomical diseases in the form of 1) minimal endometriosis(Do laparoscopy) ,2)  Tubo-peritoneal causes (do laparoscopy) , uterine factors(SIS/ hysteroscopy) ,3)  raised BMI (estimate BMI weight in Kg/ Ht in cm²,  4) Endometrial koch’s(hysteroscopy )  and 5) persistent thin ET 6) Luteal phase defect 7) coital factor too. Hypothalamic-PIT diseases are rare possibility in regularly menstrual cycles.. DHEASO4 should be estimated on Day 3  for establishing Adrenal androgen excess and planning for corticosteroid Ry. WE should diligently search for clinical evidence of hyper androgenism( Acne, hair loss) and or hyperinsulinaemia ( High W/H ratio, Acanthosis )

What next tests after CC failure/ CC resistance ?? Examples of such tests are, 1)  PRL, 2 ) Metabolic disorders, 3)  . Day 3 LH,4)  FSH, 5) E2,  6) AMH    7) AFC   8) DHEASO4 and 9)    ? High day 9 LH. 10) Lapro-Hysteroscopy if thetre is palpable mass or tenderness or clinical evidence to suggest pelvic adhesive diseases,   minimal endometriosis SIS is another alternative 11) Similarly review of semen some other reputed Lab  &  12 ) PCT under your control may be thought of.     All tests   will be cost apporx Rs 20,000/- (if one does not go for lap hyst then cost will come down to Rs 7000/ approx. But in subfertility treatment time is essence. Earlier she becomes mother it will be medically easy for parents to rear up the child/ children including health supervision education. Further, every futile ovulation induction cycle  invites disappointment and frustration to the couple

.

Few are of opinion that results of induction may be superior with Enclomiphene dosage schedule from day 2 to day 6 one tab od 50mg than total clomiphene but opinion varies

Prevention of Diabees-Is it possible??

·         Prevention of T2D Is it a still a myth ?? : In Indian study it was revealed that behavior modification can slow the progression to T2D but can’t prevent the DM .Not only Lifestyle but metformin independently reduced progression of IGT to T2DM but can’t prevent its onset. The diabetes prevention trials, in general, involved intensive individualized interventions. Translational research has shown that less expensive, group based lifestyle interventions are also effective in achieving weight loss, thereby reducing risk of T2D.
Prevention of T2D is undoubtedly cost effective. Several large clinical trials have demonstrated that T2D can be delayed or prevented by lifestyle intervention or medications. Most of these studies involved subjects with impaired glucose tolerance (1GT). Almost 40-50 % of those with IGT progress to T2D during their lifetime. Firstly, one should change her/ his Lifestyle Intervention
One of the earliest trials, Study 1:-The Da Qing study in China, demonstrated reduction in risk of T2D with diet, exercise or both, risk reduction by 31-46 %. Study 2:- The Finnish Diabetes Prevention Study (DPS) showed a risk reduction of 58 % at 4 years in the intervention group compared to controls. It involved 522 subjects and the intervention targeted at five goals; (1) modest weight loss of 5 %, (2) decrease fat intake to <30 %, (3) decrease saturated fat to <10 %, (4) increase fibre and (v), moderate physical activity of at least 30 min per day. Furthermore, the DPS demonstrated that the reduced risk was proportional to the number of lifestyle goals obtained.’ Study 3 :-The Diabetes Prevention Program (DPP)one of the largest randomized control trials, studied 3,234 American multiethnic obese subjects with IGT with a median follow-up of 2.8 years. It showed similar risk reduction of 58 % with intensive life style as in DPS. It has to be noted that in all the above trials, (the benefit persisted for several years after cessation of active intervention. Study 4:- The Indian Diabetes Prevention Program (IDPP) also showed that lifestyle and metformin independently reduced progression of IGT to T2 Dm though the above trials have proven that behavior modification can slow the progression to T2D. the intensive personal contact methods used by them may not be universally adaptable due to inadequate resources. Reassuringly,
a recent study in India has demonstrated that less expensive methods like mobile phone messaging can be successfully used to reduce the risk of T2D. Study 5 :-In this randomized controlled trial, lifestyle advice through regular text messaging was acceptable to the participants and reduced the risk of progression to T2D by 36 % over 2 years. As the study was conducted on working men with impaired glucose tolerance in an urban population, it remains to be seen if it is acceptable and effective in other populations. However it is an exciting prospect considering the rapid increase in mobile phone ownership, particularly in developing countries with poor health care infrastructure where the impact can be substantial.
Medications for overt DM:- No medication is licensed for use in, those people at high risk of diabetes.
Medications used in treatment of T2D and obesity have also been found useful in prevention, although all have significant side effects. Since not all people who are at risk of diabetes will develop diabetes it therefore becomes important to consider the risk-benefit ratio. Currently, in the UK and many' countries across the world, no medication is licensed for use in, those people at high risk of diabetes. Study 6 : Metformin at a dose of 1,700 mg/day was effective in DPP with 31 % risk reduction and the benefit was more pronounced in younger, more obese subjects and in women with prior gestational diabetes. Study 5(contd) :-The IDPP showed that metformin was also effective in a lower dose of 500 mg/day in reducing the progression to
T2D in Asian Indians. ;
Thiazolidinediones (troglitazone, rosiglitazone and pioglitazone) have proven very effective with a 50-70 % reduction m IGT conversion to diabetes in various trials, as has acarabose. though adverse effects are common.

What about orlistat ?? Orlistat in combination of lifestyle changes, reduced the progression to diabetes by 52 % when compared to lifestyle and placebo; however this drug was poorly tolerated by the participants.
What about Incretin based therapies (GLP-1 agonists and DPP-4 inhibitors) as a mode of prevention/ deferring DM?? Their role in prevention of T2D

remains largely to be explored) Such drugs are being increasingly used for their beneficial effects on weight and glycemic control in T2D, but their role in prevention of T2D

..