Leptin Is Normal in PCOS, An Editorial about Three "Negative" Papers

Jose F. Caro, M.D.

Lilly Research Laboratories Lilly Corporate Center Indianapolis, Indiana 46285

Address correspondence and requests for reprints to: Jose F. Caro, M.D., Eli Lilly Research Laboratories, Lilly Corporate Center, DC0424, Indianapolis, Indiana 46285.


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Leptin is a hormone secreted by adipocytes (1). Its main role appears to be the control of body weight through the regulation of appetite and thermogenesis (2). Also, injection of leptin into rodents increases gonadotropin and ovarian follicular development, and restores fertility (3, 4). The discovery that different isomers of the leptin receptor are present, not only in the hypothalamus, but also in peripheral tissues including the ovary, suggests that the effect of leptin on the reproductive axis could be central and/or peripheral (5).

In an attempt to indirectly learn about leptin and its effects on the ovary, polycystic ovary syndrome (PCOS) has been targeted for study; the reason being that PCOS is reminiscent of the condition present in rodents with leptin deficiency or leptin resistance (2).

The first such study on PCOS was published in this journal in November, 1996 (6). Brzechffa et al. (6) reported that a substantial proportion of women with PCOS have leptin levels that are higher than expected for their body mass index (BMI), free testosterone, and insulin sensitivity (6). These provocative results suggested that abnormalities in leptin signaling to the reproductive system might be involved in certain cases of PCOS (6).

The same laboratory recently reported that leptin inhibits the synergistic action of insulin-like growth factor I (IGF-I) on FSH-dependent estradiol-17ß production by rat ovarian granulosa cells (7). This led to a simple but provocative mechanistic explanation: hyperleptinemia contributes to infertility in some women with PCOS by counteracting the sensitizing effects of IGF-I on dominant follicles (7). Of course, this intriguing possibility is not the end of the story, but one of the reasons for this editorial.

In this issue of JCEM, three independent laboratories (8, 9, 10) provide clear evidence against the concept that circulating leptin levels are elevated in PCOS patients compared with those regularly menstruating control subjects.

The three "negative" studies reported in this journal (8, 9, 10) are very good pieces of clinical investigation. They prove the point that most of the time "negative" studies are as important as "positive" ones. The testing of a well-formulated hypothesis is the only thing that really matters.

I invite the readers to look at these three seemingly "negative" studies. I will not review them here, but just to capture your curiosity, I want to suggest to you that they are not "negative" at all. It is quite clear that, if one replots leptin vs. BMI from all subjects studied in the four published papers (6, 8, 10) (133 controls and 150 subjects with PCOS), it is not possible to detect any difference between control and PCOS.

Is this the end of the leptin vs. PCOS story? I doubt it. Instead it is only time to change or redefine the hypothesis. Let’s remember the wonderful presidential address of Dr. Fuller Albright—"The Do’s and Do-Not’s in Clinical Investigation".

"Do" No. 9. Do develop an hypothesis.

"Do-not" No. 7. Do not be a slave of your hypothesis.

Do feel hurt if your facts are wrong, not if your hypotheses are wrong.

Is the difference between Magoffin’s laboratory (6) and the three papers published in this issue a rare encounter in clinical investigation? Not at all, it just represents the difficulty of clinical investigation.

We could accept today that for a given BMI, leptin is not different in control vs. PCOS. But what about leptin vs. body composition in a large group of patients? Is it reasonable to expect that women with the same BMI but with different androgen levels would have different body composition? Also, leptin circulates in bound and free form (2). Is the proportion of bound vs. free leptin the same in control vs. PCOS? Furthermore, leptin has a circadian rhythm and circulates in pulses (2). Are there any differences between control vs. PCOS in pulsatility of circulating leptin? Finally, and most importantly, what is the sensitivity of leptin with regard to the hypothalamus-pituitary-ovary axis in women with PCOS vs. control?

Clearly, the above questions will only be answered by detailed clinical investigation and ultimately by the administration of leptin to humans. For the present, we must wait for the end of the current generation of papers, the product of the widespread "leptinomania" initiated by the development of the leptin RIA (2). It is not every decade that a new hormone like leptin is discovered. When will the next opportunity occur that will allow investigators to use those frozen plasma samples, from those subjects so difficult to recruit, for that study so carefully designed to test a nonleptin hypothesis? Perhaps soon, so please do not use all of your frozen sera for the determination of leptin.

Let’s expect and hope that the next generation of studies will be designed to test hypotheses on leptin physiology and pathophysiology.

Received March 28, 1997.

Accepted April 3, 1997.


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  3. Barash IA, Cheung CC, Weiglo DS, et al. 1996 Leptin is a metabolic signal to the reproductive system. Endocrinology. 137:3144–3147.[Abstract]
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  6. Brzechffa PR, Jakimiuk J, Agarwal SK, Weitsman SR, Buyalos RP, Magoffin DA. 1996 Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 81:4166–4169.[Abstract]
  7. Zachow RJ, Magoffin DA. 1997 Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17ß production by rat ovarian granulosa cells. Endocrinology. 138:847–850.[Abstract/Free Full Text]
  8. Mantzoros CS, Dunaif A, Flier JS. 1997 Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metabol. 82:1687–1691.[Abstract/Free Full Text]
  9. Laughlin GA, Morales AJ, Yen SSC. 1997 Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. J Clin Endocrinol Metab. 82:1692–1696.[Abstract/Free Full Text]
  10. Rouru J, Anttila L, Koskela P, Penttila TA, Irjala K, Huupponen R, Koulu M. 1997 Serum leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 82:1697–1700.[Abstract/Free Full Text]
  11. Albright F. 1997 Some of the "Do’s" and "Do-Not’s" in Clinical Investigation. J Clin Invest. 23:921–926.