PCOS is not the only reason for androgen-excess

Polycystic ovarian syndrome (PCOS) is often a convenient diagnosis for many actually suffering with other endocrine disorders. Cushing's patients are frequently misdiagnosed with PCOS. It is an easy diagnosis (in layman's terms) and avoids the multiple tests and confusion which suspicion of Cushing's seems to bring. In a previous post, I wrote about 4 cases of Cushing's misdiagnosed as PCOS. Once treated for the Cushing's, all symptoms which had been attributed to PCOS resolved.

A new article in the New England Journal of Medicine, Inactivating PAPSS2 Mutations in a Patient with Premature Pubarche, the authors show that "PAPSS2 deficiency should be added to the list of defined causes of androgen excess that must be ruled out before diagnosing the polycystic ovary syndrome."

There are two isozymes encoded by genes located on chromosome 4 (PAPS synthase 1) and chromosome 10 (PAPS synthase 2, also abbreviated as PAPSS2) which are important in the sulfation of DHEA to DHEAS. DHEA is a precursor to androgens, and when the sulfation to DHEAS can not take place, the authors hypothesize this leads to androgen excess. They present the case of an 8 year-old girl with "premature pubarche, hyperandrogenic anovulation, very low DHEAS levels, and increased androgen levels." They determined she had a genetic defect which caused a loss of PAPSS2 activity. It is still unclear why the PAPSS1 enzyme did not compensate for that.

The article is well-written, very thorough, and full of graphs, pictures, and diagrams. It explains how they followed this young lady for several years, the studies they did, and the testing that was done. It also begs the question of diagnosing PCOS due to androgen excess. PAPSS2 deficiency appears to be a genetic adrenocortical cause of androgen excess.


Noordam C, Dhir V, McNelis JC, Schlereth F, Hanley NA, Krone N, Smeitink JA, Smeets R, Sweep FC, Claahsen-van der Grinten HL, Arlt W. (2009). Inactivating PAPSS2 mutations in a patient with premature pubarche New England Journal of Medicine, 360 (22), 2310-2318 PMID: 19474428


To read more:

Distinguishing PCOS and Cushing's: Does testosterone tell the tale?

Cushing's Syndrome in Women With Polycystic Ovaries and Hyperandrogenism

Germline mutations in AIP have been recently shown to cause pituitary adenoma predisposition (PAP)...

Many of the members of the Cushing's Help message boards have relatives and/or siblings who have also been diagnosed with a pituitary tumor and Cushing's Disease. Conservative, "textbook" cases of Cushing's have long been touted as nonheritable by the conservative, textbook endocrinologists. However, new research is reaching different conclusions.

In a very recent article published by the Journal of Clinical Endocrinology & Metabolism, Large Genomic Deletions in AIP in Pituitary Adenoma Predisposition , the authors make a case for large genomic AIP deletions accounting for a subset of pituitary adenoma predisposition (PAP). They state "functional evidence suggest that AIP acts as a tumor suppressor gene." The free author's manuscript is linked, but a more up-to-date version may be found in October's edition of the journal.

The study included multiple family lines from various countries, with the "selection criterion for young age of onset aimed at enriching for possible PAP cases." The authors make the claim that "[t]ypically, PAP patients have a young age at disease onset, without a strong family history of pituitary adenomas."

The patients had already been tested for MEN1, PRKAR1A and other germline mutations also responsible for Cushing's and/or adrenal abnormalities.

Eleven families were heterogeneous (different types of adenomas), and 12 were homogeneous (same type of adenoma), including seven with acromegaly/gigantism, four with nonfunctioning adenomas, and one with prolactinomas (Table 1). In addition, 39 sporadic Finnish GH-secreting adenoma cases aged 40 yr or less at diagnosis and 35 sporadic Italian pediatric pituitary adenoma patients were analyzed.

Multiplex ligation-dependent probe amplification (MLPA) was used to identify these genomic rearrangements and proved to be a very beneficial tool to search for germline copy number changes in AIP.

This type of study may lead to better clinical evaluation, treatment, and calculation of the chance of relapse. The authors go on to say "...it would be of great interest to compare the disease spectrum and penetrance in families with truncating and nontruncating AIP mutations; clearly, much larger patient series and detailed medical investigations would be needed for this."

M. Georgitsi, E. Heliovaara, R. Paschke, A. V. K. Kumar, M. Tischkowitz, O. Vierimaa, P. Salmela, T. Sane, E. De Menis, S. Cannavo, S. Gundogdu, A. Lucassen, L. Izatt, S. Aylwin, G. Bano, S. Hodgson, C. A. Koch, A. Karhu, L. A. Aaltonen (2008). Large Genomic Deletions in AIP in Pituitary Adenoma Predisposition Journal of Clinical Endocrinology & Metabolism, 93 (10), 4146-4151 DOI: 10.1210/jc.2008-1003

Obesity is a popular topic these days.....

Is it a fad or is there really such an "epidemic" of obesity that it's become the topic of the year? I really can't answer that right now because I need to study it in more depth. I do know, however, that the mainstream media can grab onto a topic and worry it like a dog with a bone. Sometimes I just want to say "bury that dead horse already". Sometimes. A lot of the time.

But I'm not opposed to talking more about obesity as long as those talking about it are willing to help come up with viable, workable reasons with solutions and stay away from the attacks. I'm not persuaded the media sees the topic as anything other than another way to make money. It's a "hot" topic. That and gas prices.

Why not put both together in one topic? Oh wait, someone did that already: Increasing Gas Prices Could Be A Good Thing.

"According to a University of North Carolina study, the end result could be a 10 percent reduction in American obesity over the next seven years."

We could even combine it with politics! Wow...now that's a topic. No, I'm not talking about the very ill Ted Kennedy. Shame on you for thinking that!

Mr. Sali also announced a draft bill to "propose that the force of gravity, by the force of Congress, be reduced by 10%" to combat obesity. Mr. Sali said it was meant to parody a bill to raise the minimum wage, which he felt ran counter to the laws of economics.

Poor Australia....they are getting hit from all sides about it. Even their pets are obese. 33% of their cats and 41% of their dogs are overweight. (Who goes around and weighs all these animals?)

No, I don't take much of the media hype about anything seriously. I do take obesity seriously though. I've been fighting it for ages. Thus, this is a problem for me. I don't trust the hype, but I do observe the problem.

On the flip side, the BBC reports: Can genes explain rising obesity?

Contrary to conventional wisdom, the obesity epidemic is not restricted to people in Western countries who eat bad diets and are not very active.

In developing countries, it is estimated that over 115 million people suffer from obesity-related problems.

Experts believe that in many of these people these problems are not due to lifestyle but a condition called metabolic syndrome...There are many uncertainties about metabolic syndrome but one thing is certain - it cannot be explained entirely by genetics or lifestyle factors.

Betcha didn't read that one anywhere recently, did you? It's not newsworthy. A student newspaper caught wind of it, though. Yes, you can tell it's a student, but the sources are excellent. Well worth reading.

"This tells us that nutrition in utero is largely responsible for our epigenetic
programming and that under nutrition in one generation could explain the rise in
obesity, heart disease and diabetes in the next! It’s a far cry from the popular
cultural view that lifestyle changes are the be all and end all determinants of
good, or poor health - that everything boils down to personal decision
making..."

As with everything, take what you are reading with a grain of salt. I even challenge you make sure the statistics that are being quoted are real statistics. Anyone can make up numbers. And anyone can write anything on the internet. Including me.