Classification of Progesterones

Classifications of Progesterones:  Family of progestins Parent compounds

A) Progesterone

1) 17a acetoxyprogestreone – Pregnane derivatives – Megestrol acetate , medroxyprogesterone acetate , Chlormadinone acetate cyproterone acetate

B) Testosterone – Derivatives – 19  nortestosterone

C)  – Estrane derivatives – Norethindrone , norethindrone acetate , Ethynodiol diacetate , Mefipristenone , norethynodrel , Tibolone

D)Gonane  derivatives

Norgestrel

Levonorgestrel

Desogestrel

Etonogestrel

Gestodene

Norgestimate

Norelgestromin

Spirolactone – 17a spironolactone – Drospirenone

Androgenic Progesterone

Primolut N at the age of 48 yrs continuously –How safe metabolically –Is Primolut N cardiac & lipid friendly??  We should note that some of the synthetic progestins (Primolut-N in your case at the age of 48 yrs) is basically a  prodrug, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered. How little we know about Progesterone at the age of 48 yrs and its role in etiogenis of breast cancer??

 What, then are the ancestor of progesterone??  Evolution of Progesterones::-History of progestins selection oral contraceptive drugs and their use :-The first hormonal pill, called Enovid, was approved by the Federal Drug Administration (FDA) in May 1960. It contained mestranol and norethisterone. Over the years, oral contraceptives have evolved through gradual lowering of ethinyl estradiol (EE) content, introduction of 17β estradiol, and many different progestins. The standard regimen allows for 21 days of pill containing steroids and a pill-free interval of 7 days. Recently, continuous or extended regimens have been approved. In order to improve compliance, alternative routes of combined oral contraceptive (COC) administration have been developed such as vaginal or transdermal routes.In 2009, according to the United Nations, the mean global percentage using contraception in women who are married or in union was 62.7%. COC represented 8.8% of contraceptive prevalence, reaching 15.4% in more developed countries. More than 100 million women worldwide use COCs. However, each year, many unintended pregnancies occur, indicating that contraception still needs to be promoted. Over the years, oral contraceptives have evolved through gradual lowering of ethinyl estradiol (EE) content, introduction of 17β estradiol, and many different progestins. The standard regimen allows for 21 days of pill containing steroids and a pill-free interval of 7 days. Recently, continuous or extended regimens have been approved. In order to improve compliance, alternative routes of combined oral contraceptive (COC) administration have been developed such as vaginal or transdermal routes.

In 2009, according to the United Nations, the mean global percentage using contraception in women who are married or in union was 62.7%. COC represented 8.8% of contraceptive prevalence, reaching 15.4% in more developed countries. More than 100 million women worldwide use COCs. However, each year, many unintended pregnancies occur, indicating that contraception still needs to be promoted.

 

Pubertal changes in girls-Thelarche, Puberache Growth surt, Adrenarche,,

Step 1:-Thelarche is the onset of female breast development. Girls usually begin puberty between the ages of 8 and 13 years old. The earliest sign of puberty in most girls is the development of breast "buds," nickel-sized bumps under the nipple. It is not unusual for breast growth to start on one side before the other. Girls usually begin puberty between the ages of 8 and 13 years old. Thelarche is the most common primary heralding sign of pubertal development. . Unilateral onset of breast development is a recognized entity, and it may take 6 months for the opposite breast bud to become palpable The Stages of  thelarche are as follows :-

·        Tanner stage 1.

·        Tanner stage 2.

·        Tanner stage 3.

·        Tanner stage 4.

·        Tanner stage 5.

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B) Pubarche is the appearance of sexual hair. Pubarche (pubic hair development),One variation in onset of puberty is the development of pubarche (pubic hair development) before thelarche.

C) Adrenarche is the onset of androgen-dependent body changes such as growth of axillary hair, body odor, and acne. .Adrenarche is usually normal in girls who are at least 8 years old, and boys who are at least 9 years old. Even when pubic and axially hair appear in children younger than this, it is still usually nothing to worry about, It's normal and healthy to gain weight while going through puberty. ... This “growth spurt” happens very quickly. On average, girls grow about 3 inches (8 cm) per year during the growth spurt. Girls usually stop growing taller about 2 years after starting their menstrual period.

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D)       Menarche is the onset of menstruation.. In general, menarche occurs 24 months after thelarche .Approximately 18 months is required between initial onset of menarche and regular ovulatory cycles. Menarche however symbolizes the onset of sexual maturity and is characterized by the onset of the first menstrual bleeding. Although there's no one right age for a girl to get her period, there are some clues that it will start soon. Thelarche is the onset of female breast development. Pubarche is the appearance of sexual hair. Adrenarche is the onset of androgen-dependent body changes such as growth of axillary and pubic hair, body odor, and acne. The average age at menarche is 13.8 years; however, it ranges from 9 to 18 years and varies by race and ethnicity On an average ,most girls get their first period when they're around 12. But getting it any time between age 10 and 15 is OK. Every girl's body has its own schedule.. Menarche is the onset of menstruation.

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What changes are observed in onset of menarche & menopause?? T

he first menstrual period, menarche, signals the beginning of the capacity to reproduce and is associated with the development of secondary sexual characteristics. Menarche is one of the most significant milestones in a woman's life. The first cycles tend to be anovulatory and vary widely in length. They are usually painless and occur without warning. Menarche occurs between the ages of 10 and 16 years in most girls in developed countries. Although the precise determinants of menarcheal age remain to be understood, genetic influences, socioeconomic conditions, general health and well-being, nutritional status, certain types of exercise, seasonality, and family size possibly play a role.

The decline in menarcheal age Lowering of age of menarche globally :Over the past century the age at menarche has fallen in industrialized countries, but that trend has stopped and may even be reversing. The average age at menarche in 1840 was 16.5 years, now it is 13. The age at menopause, however, has remained relatively constant at approximately 50 years. The length of time during which women are exposed to endogenous estrogen has therefore been increasing. Reasons for the fall in menarcheal age remain unclear, but one interpretation considers it to be a reflection of the improvement in health and environmental conditions. The decline in menarcheal age appears to be leveling off in many countries such as Britain, Iceland, Italy, Poland, and Sweden, but continues in Germany and some other countries.

Late menarche is associated with a decreased risk of developing breast cancer in later life, a decreased frequency of coronary heart disease, later first pregnancy, and reduction in teen pregnancy. Late menarche may, however, be positively associated with the risk of developing Alzheimer's disease.

Hirsuitism

•     Hirsutism- Tips & Tricks in establishing the etiology of hirsutism.

•     A) What are the phases of NORMAL HAIR GROWTH:-- There are  three classical phases of hair growth- e.g.  Anagen-growth phase; Telogen-resting phase. Catagen- the involution phase.

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•      B) Prevalence of hirsutism is 5-10% of all reproductive age women. Of  all hirsute 57-82% are due to PCOS amongst reproductive aged women &   the other way round  prevalence of abnormal hair growth in PCO is  about 6-10%.

•      In PCOS both ovarian and adrenal androgen contributes in the causation of excessive growth of terminal hairs as is usually seen in males. Hair growth(growth of terminal hairs)  in some  areas of body is considered as abnormal for a woman.

•     C) What are Vellus hairs as is observed in  some areas of body in both men &women .These are fine, no pigmented, short hairs normally present in the healthy female too    ?? These vellus   hairs  responds to circulating androgens very poorly (virtually insensitive) but capable of resending only when serum Testosterone is very much raised.   

•     Such areas where seldom if ever pigment hairs are  seen in women are   Truncal    area of body, particularly back of trunk. The moment a  clinician  see  presence of dark, thick pigmented nonvellus hairs then the immediate diag in woman is “Abnormal Hair Growth” due to androgen excess diosrder  and can’t be due to familial or of PCO origin.  These sites Chest , more importantly back of scapular region , midline  trunk) allow growth of Terminal, black, coarse hairs    only in presence of high dose of androgens.

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•      What are the androgen dependent areas of the body?  Ans:-Upper lip, thighs ,legs, forearms, Chin, mid abdomen , front of chest, and back in that order – the last three sites  are the sites where  if hair is visible then it is unlikely to be familial  and through evaluation is mandatory. Which area of body responds to only high dose of androgens and therefore mandates thorough investigation? Back of trunk & scapular region, gluteal region.

•     D) Where does androgen works? Androgen effects on hair vary in relation to specific regions of the body surface. Hair that shows no androgen dependence includes lanugo, eyebrows, and eyelashes. Excessive hairs present in these areas, therefore mandate no investigation

•     E) Which are the body sites where hair growth should be considered abnormal? Back of trunk, Scapular region & Moustache.

•     What about  hairs located at Beard region ,  Infra-mammary area. Inner thighs. Midline  lower back,. Ans:-In these sites , Vellus hair ( fine, no pigmented, short hairs normally present in the healthy female too)à is converted to  Coarse, Stiff, Pigmented and long hairs  àcalled Terminal hair, only if androgen level is high  and or 5a-reeducates is high locally.

•     G) Etiological Diagnosis of Hirsutism: - The diagnoses of Hirsutism are like a diagnosis of PCOS.

•     By exclusion of different diseases, at least 5 common and 5 uncommon diseases/syndromes have to be excluded by different tests.

•     But majority start treatment with serum Testosterone and DHEASO4 tests only.

•     I) am presence of hirsutism is associated with menstrual disorders/ Weight IN Oligomeno /infertility: - When hirsutism is accompanied by absent or abnormal menstrual periods, assessment of prolactin and thyroid-stimulating hormone (TSH) values is required to diagnose an ovulatory disorder.

•     H) Excess Androgen causes:-evidence of Virilizism/, Clitoromegaly, Clitoral index or muscle wasting or Acanthosis Nigricans (which usually speaks of IIR & Metabolic Syndrome) and Striae in abdomen.

•     I):-Is hirsutism associated with any Metabolic Markers? If there is evidence of overweight/ frank obesity, Acanthosis, increased Waist/ Hip circumference then one should consider assessment of metabolic parameters  (indices of glucose metabolism combined with lipid profile) was offered to all such suspected cases to confirm or refute the diagnosis of PCOS.

•     J):-Associated with subfertility problem? Hirsutism is an incidental finding? Hypothyroidism and hyperprolactinemia may result in reduced levels of SHBG and may increase the fraction of unbound testosterone levels, occasionally resulting in hirsutism as an incidental finding.

•     Therefore, estimation of TSH & PRL (pooled sample) is essential part of initial endocrine evaluation of hirsute cases.

•     K) Correlation with serum Testosterone:-Total Testosterone > 200 ng.
/ml à Adrenal Tumours. Total testosterone:-

•     A) 80-150 ng/dl= PCOS, Hyperthecosis or > HAIR-A Syndrome.

•     B) Total Testosterone: > 200= Cushing's syndrome.

•     But:-Estimation of Total T has limited value unless there is gross virilization. The reason is that the disease which has caused raised production of T may also quantitatively modify the SHBG production. Total Tester one  estimation, therefore without‘

•     Estimating “a) AT- Albumin – bound to Testosterone and b) SHBG may be    less informative. In clinically presumptive hyperandrogenic states (where increased production of Testosterone from any source –e.g. Ovary, Adrenal, Adipose tissue) is not parallel   reflected in serum Tees.  The way/methodology by which we commonly assay. Paradoxically in most cases where hyperandrogenemia is suspected clinically, result come as normal serum Total Tees. Due to concomitant alteration of SHBG level. In my opinion at least 10% of all IVF failure is due to adrenal hyperandrogenism which is only partly taken care by down regulation.

•     How best to diagnose Androgen Secreting Adrenocortical Tumours? This line of investigation has to be considered when the androgen excess reaches the point of virilization. To put in biochemical terms àthe free T in such cases should be >6.85 pg/ml (i.e. 23.6 p mol/Lit) à then follow up with 11-desoxy-cortisol which will be > 7 ng/ml & DHEAS > 3.6 mcg/ml. A 24 urinary cortisol in such cases will usually be > 45 mcg/day.

•     How best to diagnose Congenital Adrenal Hyperplasia? Elevated 17-hydroxyprogesterone (17-OHP) levels identify patients who may have AOAH, found in 1% to 5% of hirsute women. The 17-OHP levels can vary significantly within the menstrual cycle, increasing in the periovulatory period and luteal phase, and may be modestly elevated in PCOS. Standardized testing requires early morning testing during the follicular phase .How best to diagnose CAH? According to the Endocrine Society clinical guideline, patients with morning follicular phase 17-OHP levels of less than 300 ng/dL (10 nmol/L) are likely unaffected .When levels are greater than 300 ng/dL but less than 10,000 ng/dL (300 nmol/L), ACTH testing should be performed to distinguish between PCOS and AOAH. Levels greater than 10,000 ng/dL (300 nmol/L) are virtually diagnostic of congenital adrenal hyperplasia.

•     L) How best to - Stepwise endocrine evaluation will save money? Concentrations of LH, FSH, LH/FSH ratio, testosterone, free testosterone, SHBG and insulin in serum were recorded in 32 women with PCOS and in 25 controls. A model including LH/FSH ratio, insulin and testosterone measurements yielded the best goodness of fit for classification of women with and without PCOS in the logistic regression analysis. Only LH/FSH ratio and insulin were retained as significant variables. The diagnostic characteristics of LH/FSH ratio and insulin for PCOS when compared by receiver-operator characteristic analysis were found to be equally effective. By combining these two variables a higher area under curve was obtained. LH/FSH ratio, insulin or the combination of these two can predict the disease probability in women with PCOS.

•     What is F-G Score? A clinical score of hirsutism??

•      If above> 9 (as is in this case) we proceed for 24 Hr. urinary cortisol starlight way. Not only raised FG Score if there are clinical S/S of Cushingoid feature like Moon faces, Plethora, supra clavicular pad of fat. We always proceed for such test at the outset without wasting much time. If Report> 45 mcg/day-then we should better send her to Endocrinology Deptt. and the immediate diag is Cushing’s, -further tests to follow at medicine Deptt.

•     If the F-G Score is   less than 8:- we perform Urine for preg test in initial visit →-Progesterone withdrawal bleed -→on day 3/4/5 of bleed we estimate traditional/conventional tests for hirsutism e.g.  PCOS.AIAH, HAIR-A syndrome profile.

•     What initial Lab Tests? TSH, Prolactin, Androgens (Total and if possible free Testosterone, DHEASO4, 17-OH Progesterone), 24 Hrs. UFC (urinary Free Cortisol), and Pelvic ultrasound. OGTT, Lipid Profile as necessary

•     Routine Tests. 3) PRL, 4) TSH and 5) PP insulin and PP sugar a-2 hr. after 75 gm.of   Glucose load.

•      6) However in case Total testosterone (which has diurnal variations) has been estimated elsewhere and report come as >200ng/ml (200ng/dL) then also one should seriously consider the possibility of OV/Ad tumours.

•     Tests include 1) 17-OH Prog, (to exclude late onset CAH-if report is >250 mcg/dL-)-this test should ideally be carried out early morning, but Lab seldom are ready by this time. 2) DHEASO4( if this >60000 ng/ml then we have to consider adrenal/Ovarian   tumours .

•     F-G Score is   less than 8:--Tests include 1) 17-OH Prog, (to exclude late onset CAH-if report is  positive  if  report  is >250 mcg/dL-)-this test should ideally be carried out  in early  morning, but Lab seldom are ready by this time. 2) DHEASO4( if this >60000 ng/ml then we have to consider adrenal/Ovarian   tumours  . However -in our deptt we include imaging of ovaries and Adrenals if there are such warning values(backed up by coarse hairs at scapular regions, inner thighs and gluteal regions).  Additionally it  is our routine practice to undertake following tests as most of such exceeds of Androgen Excess Disorders  do present with   sec ameno and on careful exam clinicians observed abnormal  pigmented hair growth ..Such tets are routine doe sec ameno like →3) PRL,  4)TSH and  5) PP insulin and PP sugar a-2 hr. after 75 gm. of  Glucose load . ‘

•      However in case Total testosterone (which has diurnal variations) has been estimated elsewhere and report come as >200ng/ml (200ng/dL) then also one should seriously consider the possibility of OV/Ad tumours. and proceed for imaging modalities forthwith without asking repeating the tests. Similarly  if Free Testosterone  is at all estimated elsewhere –we shall be paying due importance only if it is contemplated by   EQUILIBRIUM DIALYSIS METHIOD which is the standard method of estimating Free Testosterone.. If such report is between 10-30 pg/ml it is likely to be PCOS rather than ad/Ov tumours. I understand there are many more indirect methods of assaying free Tees. I wonder why now a day’s Modified F-G Score is not followed in most of OPD sheets/ Prescription pads in Pvt clinics.!- 

Cerebral palsy

Definition of cerebral palsy:--

Cerebral palsy (CP) is a group of disorders of movement and posture caused by a nonprogressive lesion of the developing brain . Clinical features such as spasticity change over time  .It (CP) describes a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, and behaviour, by epilepsy, and by secondary musculoskeletal problems. Cerebral palsy is the most common cause of motor disability in childhood, affecting about 2 per 1000 live births in high resource settings. Over the past few decades, there have been major changes and advances in obstetric and neonatal care, with a decline in neonatal mortality. The prevalence of CP has been shown to be constant over time by several studies; however, the at-risk population and subtypes observed appear to have changed. The pooled prevalence of CP across studies from North America, Europe, and Australia is 2.11 per 100 live births (95% CI 1.98–2.25)

A)             Epidemiology: Cerebral palsy may be difficult to diagnose before 1 year of age and, in some children, prior to 2 years. Pathophysiology

B)              Site wise symptoms nad signs: Why & how it happens?? Cerebral palsy results from an insult to a part of the brain associated with motor control, with the region affected determining the clinical signs and classification. Thus, with spastic cerebral palsy, the brain areas most affected are the cerebral cortex and corticospinal tracts. In this condition, spasticity occurs because of hyperactivity of the stretch reflexes that result from the lesions of the corticospinal tract that cause uncontrolled facilitatory input at the spinal reflex arc.

The basal ganglia is the brain area most affected in dyskinetic cerebral palsy. This brain region is a major component of the extrapyramidal system that plays a role in controlling automatic movements, movements associated with posture, and fine digital movements. Basal ganglia lesions result in abnormal involuntary movements such as athetosis and dystonia. CP may be of Neonatal hyperbilirubinemia can cause dyskinetic cerebral palsy through the neurotoxic action of unconjugated bilirubin on the basal ganglia.

The cerebellum, which coordinates movement, or its associated pathways are most affected in ataxic cerebral palsy. Lesions in this area result in ataxia, difficulty with balance and proprioception, intention tremors, and dysmetria.

Male sexual diorders

L

Europeans.

Apprehension about the normal size of penis is a major concern for men. Aim of the present investigation is to estimate the penile length and circumference of Indian males and to compare the results with the data from other countries. Results will help in counseling the patients worried about the penile size and seeking penis enlargement surgery. Penile length in flaccid and stretched conditions and circumference were measured in a group of 301 physically normal men. Erected length and circumference were measured for 93 subjects. Mean flaccid length was found to be 8.21 cm, mean stretched length 10.88 cm and circumference 9.14 cm. Mean erected length was found to be 13.01 cm and erected circumference was 11.46 cm. Penile dimensions are found to be correlated with anthropometric parameters. Insight into the normative data of penile size of Indian males obtained. There are significant differences in the mean penile length and circumference of Indian sample compared to the data reported from other countries. Study need to be continued with a large sample to establish a normative data applicable to the general population.The inability to maintain an erection while having sex haunts men more than anything else and half the questions we receive on our Q&A section ask for tips to deal with this condition. Technically speaking, an erection is caused due to the hydraulic effect of blood entering and being retained in spongy bodies within the penis. In most males, this happens when they’re sexually aroused thanks to signals transmitted from the brain to nerves in the penis. Both the brain (to send a signal) and the heart (to pump blood to the penis) must work properly to get and maintain an erection. ED occurs whenever any of the proceedings are disrupted.

Impotence and infertility are not the same

Sometimes, perhaps due to similar vernacular words, people tend to use the terms impotence and infertility synonymously. It’s important to understand the difference. Impotence is the inability to get an erection whereas infertility (or sterility) is the inability to father children. They are not related or synonymous in anyway.

So what causes ED?

The various causes of ED but they can be broadly categorized under two categories: Physiological or physical (pertaining to the body) and psychological (pertaining to the mind)

Physiological Causes of ED

There are various things that we do to our body that can cause impotence:

Alcohol-consumption, smoking and drugs: The cliché sex, drugs and rock ’n’ roll is actually very wrong. Substance abuse makes it hard for your heart to pump blood and it also robs your off your libido. Drinking and drugs can cause temporary and permanent ED. While temporary ED goes away when we aren’t under influence, research has shown that as many as 60-70% heavy alcohol consumers suffer from permanent erectile dysfunction. Smoking too is a big culprit; it’s the biggest cause of ED among men under 40. In the long term, all these activities constrict your blood vessels and prevent adequate blood flow to the penis.

Diabetes:  Around 50% men with diabetes suffer from ED. In fact ED is one of the most common symptoms of diabetes. The elevated blood glucose level and nerve damage leads to inadequate blood flow and nerve damage to the penis.

Obesity: Another big reason is your extra girth (not in the right places) and not just because of low self-esteem. Most fat men tend to have high cholesterol which causes clogged arteries and prevents efficient blood flow. They also tend to have heart disease, hypertension, diabetes, higher stress levels and other obesity related issues which don’t bode well for your penis.

Medicinal Side-effect: ED can be a side effect of many common medicines such as blood pressure drugs, antihistamines, antidepressants, tranquilizers, appetite suppressants.

Other diseases and conditions that might cause ED: Diseases like high blood pressure, nerve disease or nerve damage, multiple sclerosis, atherosclerosis, and heart disease-account for the majority of ED cases. Spinal cord and brain injuries, nerve disorders such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and stroke. Sometimes surgery, especially radical prostate and bladder surgery for cancer causes ED.

Besides the aforementioned physical causes of ED there might be some psychological causes as well. Men who are suffering from depression, anxiety-related conditions and other mental health problems tend to suffer from the disease. Drugs used to treat these conditions like anti-depressants can also cause problems.

While sex is a great stress-buster, the opposite is also true – stress can lower your libido and cause ED. Actually, stress is often synonymous with physical conditions like obesity, heart disease, hypertension, etc. Some simple lifestyle changes, exercising regularly, getting enough sleep, taking some time off and seeking professional help in extreme cases can help you get over stress-related ED.

Sometimes the problem can lie in your mind. Scores of porn viewings and urban myths give guys the idea that sex is supposed to be a certain way and when it doesn’t happen exactly like they saw onscreen it can affect them. It can lead to performance anxiety and snowball into a major self-esteem issue. The most important thing to remember is that sex is supposed to be simple and fun. Just be comfortable with what you’re doing, you don’t need to strut like a porn star.

Treatment for impotency

Prescription medications such as Viagra, Cialis, and Levitra all treat the condition. All three of these medications work the same way, by helping increase blood flow to the penis. The medications are taken a half hour before sex and the effects can last from 4 to 5 hours. However these drugs all have serious side-effects and it is important to talk to your doctor and discuss your entire medical history before taking any of these drugs. As a last resort there is a surgical procedure which involves the implantation of a prosthetic device in the penis. A similar method is used in female-to-male sex change operations.

ED due to psychological reasons can be overcome by visiting a psychiatrist who can help us get to the root of the problem. We usually find the notion outrageous, that we discuss our sex life with strangers, but professional help is the best way to deal with the condition. And lastly the best solution is the simplest – talk to your partner about it.

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