Category Archives: Endocrinology

Hormones and the Endocrine System

Two days ago the new book has gone to the producer. It will be on the market in the middle of 2015. This version is in its major parts a translation of the 3rd German Edition with corrections with respect to invertebrate hormones. 

We are facing now a new production process. Whereas up to the 2nd edition the publisher took the pdf version for production, now they take the raw LaTeX files and translate them into XML. This process is not automatic and the LaTeX macros are not fully supported. Therefore the 3rd edition was more expensive than envisaged. To overcome these problems, I took care and succeeded to provide a XML version which can be then translated into any format you wish. The XML is far from perfect, but there should be something to do for the producer. However, it is complete and has all the references, and cross references, any figure (chemical structures included) either as png or in pdf and svg format, the citations and the index. Large part of it have already been expertly edited by Springer’s copy editor Stuart Evans. Thanks to everyone who provided information and expertise for the content and the LaTeX process.

“Sport ist Mord”

Obviously there is no easy translation for this German proverb: No sports, no sports is what Churchill said. Sport’s a killer, sport is murder doesn’t have the rhyme the German version has. Nevertheless, the people who say so are totally wrong. Exercise was the base that the human race could go where we are now, a overweight race with many problems due to sitting most of the time in our desk chairs while exercise is beyond the horizon and reserved to leisure. It had been just the opposite: running and hunting was the professional occupation and sitting at the fire the leisure. How time changes!

I was lead to this excurs by a review in Cell: Integrative Biology of Exercise by Howard and colleagues from Melbourne (Australia), Rochester (Maine), and Stockholm (Sweden). They bring the different aspects of Exercise into an systematic overview and nail the “Major Signaling Pathways Involved in the Control of Skeletal Muscle Hypertrophy and Mitochondrial Biogenesis” down to one image. Exercise involves “Complex and Redundant Physiological Control” in CNS, muscles, heart, lung, in the metabolism and neuroendocrine systems. The pictures are straight forward and very instructive. 


Once a month …

The selective activation of only a few of several hundred thousands primordial follicles to mature into an oocyte is a riddle which has not at all been solved. In a paper in Current Biology Chang and colleagues from Gothenburg, Sweden, place this decision onto the microenvironment of the primary cell, especially the few primordial follicular granulosa cells surrounding each primordial follicle. They show that mTORC1 activation and Kit ligand signalling are required steps in the activation, mTORC1 defective animals never develop primary follicles, the primordial follicular cells die.

They do not answer the question which follicle is to grow, but placing the decision to the surrounding is a paradigma change and will focus the experiments and the discussion away from the oocyte precursors which cells seems more or less “only” to react to the surroundings. Given that this cell is dormant and needs strong signals to be activated this is comprehensible. At least we know now who the cascade of events is initiated.

Whether this has consequences for in vitro fertilization we will see. The question why so few follicles are activated during the reproductive life of women is not answered by this article.

Nice and recommended!

Dechlorination — how it works

In Science this week there is a paper by Brommer et al. from Berlin and Jena, Germany, who reports the structure of the enzyme dehalogenase from
Sulfurospirillum multivorans in complex with trichlorethane and a pseudo-vitamine B12 providing the cobalt ion for electron transfer. A Perspectives article by E.A. Edwards further explains the findings: the pseudo-vitamine B12 is protected from the outside by the dehalogenase and a channel of open for the substrate and its analog.

Oxytocin for pairing — in mice

Oxytoxin is the hormone of social interactions, the mechanism of the interaction mostly unknown. Therefore, it is a nice surprise that Nakajima, Görlich, and Heintz from the Rockefeller Univ. in New York report in Cell on a newly identified subset of somatostatin interneurons from the prefrontal cortex of mice which bear the oxytocin receptor.

They silenced then this receptor in some mice. The females in these silenced mice with the  oxytocin receptor inactive lacked the social interactions with male mice only during the estrus phase, when copulation would ensure progeny. The interactions with female mice were normal. In the diestrus phase interactions with males  were not disturbed.

Similarily they could produce mice where the oxytocin gene was removed in the prefrontal cortex. The female mice showed the same deficit. Even mice treated with an oxytocin antagonist blocking the action of oxytocin had the same effect on the social interactions of the females thus treated.

We do not know whether oxytoxin is acting here in an endocrine way via the blood or as a neurotransmitter via synapses. It is not to far fetched to think oxytocin stimulating these interneurons is required – in mice – for social interactions leading to progeny although it is not in the paper.

A nice bit of information!

Phtalate exposure during pregnancy impairs insulin signalling – at least in rats

Phtalates are present in many plastics as softener and thus ubiquitarily distributed. They have been regarded as endocrine disruptors that means they will bind to for example the estrogen receptor and trigger that molecule to start gene activation. That has been shown for quite some time.

What is new in the paper of Rajesh and Balasubramanian in the Journal of Endocrinology is the detail of the analysis: They have looked for glucose in di(ethylhexyl)phthalate (DEHP) treated mothers and their pubs and found elevated glucose, as well as glucose and insulin tolerance. The analysis went to the insuline receptor, the insulin receptor substrate, to the glucose transporter, to all the molecules thought involved in the regulation of insulin and glucose. But not the proteins alone, the RNAs were measured, even the methylation of the DNA was estimated. And the message is very clear: with DEHP exposure in utero you will encounter a disturbed metabolism throughout life.

While this is true for rats I might be another situation in humans, but would you risk your kids health on the assumption that man is not a rat?

Nicely done! Worth reading!

Clock gene necessary for implantation

Endocrinologists are aware of the circadian clock since it determines the release of many hormone likewise cortisol in a daily rhythm. There are other rhythmic hormone releases not dependent on the circadian clock, for example the prolactin release in a circannual fashion, or faster pulses for hormones of the pituitary with one to three hours pulse lengths.

In short, the circadion clock is found in the supraoptic nucleus of the hypothalamus and concists of the RNAs and proteins Per, BMAL, Clock, and cryptochrome(s). These are generated and inactivated in a way that autonomously repeats about every 24 hours. It can also adjust to a light-dark cycle.

What is new in a paper by Liu et al. from the Bradfield labaratory at the Univ. of Wisconsin in PNAS is that steroidogenesis — the synthesis of steroids –is coupled to the clock protein BMAL-1. They show that female mice which fail to express the BMAL protein in steroidogenic cells are not capable to implant an fertilized egg into the uterus and fail to generate progeny. When they transplant one normal uterus into these animals  by exchanging one defective with the normal one, these mice will again produce offspring. The defect can, in addition, be rescued by soluble progesterone which shows that progesterone is a determining factor in nidation/implantation.

These experiments are nicely done. The conclusion, however, that  the hormone production in the ovar is decisive is too far fetched: They have eliminated the entire steroidogenesis in these mice,  therefore the only hormone producing organ of the rescued animals is the transplanted normal ovar. Progestone or other steroid hormones being soluble and acting far away from their place of synthesis could under normal conditions be generated in the adrenal or somewhere else as well. The ovar is by far not the only organ with progesterone synthesis. It will be difficult to answer the question whether the ovar’s progesterone synthesis is required for implantation, since a block in the progesteron synthesis will likely block androgen, estrogen and corticoid synthesis. You would need the 3ß-hydroxysteroid dehydrogenase 1 inactive only in the ovar. And still the animal needs androstendione substitution to allow ongoing testosterone and estrone and thus estradiol synthesis.

Worth to read!

Implantation revisited

Successful fertilization is only one half of the coin, implantation is the other half that is necessary that pregnancy can begin. As it is extremely difficult to observe normal human implantation not only for experimental, but for ethical reasons, too, the mouse is for several reasons the model of choice: implantation to occur at the blastocyst stage, only a narrow window for reception, decidualization of the stroma, invasion of the embryo into this stromal bed and a common hemochorial placentation.

In an excellent review in Molecular Endocrinology, Pawar, Hantak and Bagchi have summarized the actual knowledge about mouse implantation biology: crosstalk of estrogens and progesterons for proliferation and differentiation, estrogen and progesteron receptors at the start of signal cascades, paracrine factors as LIF, IHH, STATs, FGFs and EGF, the role of the stroma and the epithel. How the (experimental) lack of some of these proteins leads to infertility is convincingly described. It has not been a great surprise that they offer a explanation for endometriosis the disease where there is aberrant decidualisation in the peritoneum of women patients.

A must for gynaecologists!

A StAR is everywhere!

Steriod acute regulator protein (StAR) is the protein involved in the time-limiting step of stereogenesis since one molecule StAR must be produced to transport one molecule cholesterol  from the cell membrane to the mitochondrium. There, the side-chain cleavage enzyme converts the cholesterol to pregnenolone to begin the steroid synthesis for androgens and estrogens, mineralocorticoids and cortisols. StAR is therefore an important molecule for the Endocrinologist. Whereever StAR is expressed, steroids are supposed to be made. Its characteristic structure – a pocket to acquire just one molecule of cholesterol – has been crystallized and determined by X-ray spectrometry. What is much less known that it has homologues throughout the animal kingdom, even other taxa share the structure which is thus fairly old and that is used not only for cholesterol, but for numerous lipids, too.

Strange enough, a molecule which is at the beginning of a specialized reaction chain such as steroidogenesis is widely used. Sometimes the introduction to an article is an eye-opener: In Current Biology the paper by Schrick shows just such a case. They are concerned with StAR homologues in the plant Arabidopsis and their role as transcription factors. Maybe not so interesting to the general audience, but the introduction resumes the role of StAR and StAR-like proteins fairly well. Recommended.

Seasonal Regulation of Endocrine Functions.

Almost any animal regulates its metabolism as well as its reproductive life according to the time of the year. (The fact that some domestic animals do not is the exception). This dependence on the season has long been a mystery for endocrinologists. Even then it was found that the Nucleus suprachiasmaticus in the hypothalamus controls and generates a circadian (daily) rhythm which is reflected in all animals analyzed the circannual (yearly) rhythm remained obcur.

Recent developments have shown that some pituitary cells in Pars tuberalis (PT; close to the pituitary stalk) measure the length of day via the melatonin they receive. Since melatonin is only produced in the dark, much melatonin means long nights and few melatonin means short nights. These cells therefore have been named calendar cells.

In an Open Access review in the Journal of Endocrinology Shona Wood and Andrew Loudon have summarized what is known about the physiology and biochemistry of this circannual regulation. They show that thyriod hormones and their conversion from thyroxine to triiodothyronine by deiodinase are an important part in the short day response. They analyse the melatonin response in the PT. They also show how clock genes are differential regulated during the seasons. Finally they show that a ancient gene, the eye absent protein 3 (EYA3) is specifically upregulated when the days get longer.

These genes are ancient and found in insects as well as in birds and mammals pointing to a very old mechanism.

Nice paper, worth studying!