Fetal growth, length of gestation, and polycystic ovaries in adult life

doi:10.1016/S0140-6736(97)06062-5

The Lancet

Volume 350, Issue 9085, 18 October 1997, Pages 1131-1135

https://doi.org/10.1016/S0140-6736(97)06062-5 Get rights and content

Summary

Background

Polycystic ovaries are a common disorder associated with menstrual irregularities, subfertility, hirsutism, acne, and a range of endocrine abnormalities, including high concentrations of plasma luteinising hormone (LH) and excessive androgen production. The pathophysiology is not understood. We investigated whether the disorder originates during intrauterine life.

Methods

We examined 235 women aged 40–42 years who were born in Sheffield, UK. We related the prevalence of polycystic ovaries and the plasma concentrations of gonadotropin hormones and androgens to the women's body size at birth, and the length of gestation.

Findings

49 (21%) of the women had polycystic ovaries. We defined two groups of women with the disorder, which correspond to the two groups that commonly present clinically. The first group comprised obese women who were androgenised, with higher than normal concentrations of plasma LH and testosterone. These women had above-average birthweight and were born to overweight mothers. The second group comprised women of normal weight who had high plasma LH, but normal testosterone concentrations. These women were born after term (40 weeks' gestation).

Interpretation

The two common forms of polycystic ovary syndrome have different origins in intrauterine life. Obese, hirsute women with polycystic ovaries have higher than normal ovarian secretion of androgens that are associated with high birthweight and maternal obesity. Thin women with polycystic ovaries have altered hypothalamic control of LH release resulting from prolonged gestation.

Introduction

Polycystic ovary syndrome is a common disorder in which multiple ovarian cysts are associated with menstrual disorders, subfertility, hirsutism, and acne.1, 3 The endocrine abnormalities associated with polycystic ovaries include higher than normal gonadotropin concentrations, with high concentrations of plasma luteinising hormone (LH), a high ratio of LH to follicle-stimulating hormone (FSH), and excessive androgen production.3, 4 Some women with polycystic ovaries are insulin resistant5, 6 and have abnormal lipid profiles;⁷ these women tend to have enlarged ovaries, and about 50% are obese.⁸ The origins and pathophysiology of the syndrome are not understood. Hypotheses to explain it include an abnormality in the hypothalamic-pituitary control of gonadotropin-hormone release,⁹ a disorder within the ovary,10, 11 and primary roles for androgens and insulin resistance.5, 8

Since the abnormalities associated with the disorder, including hirsutism, appear around the time of puberty, the disorder probably begins in childhood.¹² Two sources of evidence, in human beings and animals, suggest it may originate during intrauterine development. In women, ovarian disease and components of the polycystic ovary syndrome are associated with altered growth in utero and during infancy. A 1995 study reported that girls with high growth rates during infancy had increased risk of ovarian cancer, which could reflect life-long alterations of the patterns of gonadotropin-hormone release that are established in utero and subsequently affect infant growth and cancer risk.¹³ By contrast, insulin resistance and lipid abnormalities are associated with low birthweight and low rates of infant growth; these associations could reflect persistence into adult life of fetal metabolic adaptations to undernutrition.¹⁴ Observations in animals strongly support the hypothesis that abnormalities of gonadotropin-hormone secretion are initiated in utero. 50 years ago, experiments in rats showed that the pattern of gonadotropin release by the hypothalamus is programmed by the concentration of androgens during early development.15, 16 Female rats exposed to high androgen concentrations have persisting changes in sexual physiology, including anovulatory sterility and polycystic ovaries.17, 18

To investigate whether polycystic ovaries originate during intrauterine life, we examined a sample of middle-aged women born in Sheffield, UK, whose size at birth was recorded in detail.

Section snippets

Methods

At the Jessop Hospital for Women, Sheffield, UK, a standard record is kept for each woman attending the antenatal clinic and labour ward. We obtained data on 968 pregnancies that resulted in a female baby being born alive between 1952 and 1953. The data included mother's weight in pregnancy, infant's birthweight, placental weight, crown-heel length, and head circumference at birth, and completed weeks of gestation from the date of the last menstrual period. We used the NHS Central Register to

Results

235 (89%) of the women invited to attend the clinic accepted, representing 68% of the original sample of 345. Their ages ranged from 40 to 42 years. 49 (21%) had polycystic ovaries. 12 had plasma FSH concentrations greater than 25 IU/mL and could therefore be classed as perimenopausal. The 49 women with polycystic ovaries had a higher frequency of irregular menses, acne and hisutism, and greater mean ovarian volume than the women with normal ovaries—though the differences were significant for

Mothers' weights

The mother's weight in pregnancy was recorded for all except four women, and, as expected, was strongly related to birthweight. Birthweight increased by 0·2 lb (0·09 kg) for every 10 lb (4·5 kg) increase in the mother's weight (p<0·001). We used the first recorded weight, taken on average at 17 weeks of gestation, though results changed little if weights later in pregnancy were used. Since the mothers' heights were not recorded, we were unable to calculate body-mass indices. The percentage of

Symptoms

We examined the symptoms of women with polycystic ovaries in relation to their birthweight and length of gestation. Four (20%) of the 20 women who weighed more than 7·5 lb at birth had hirsutism, and 13 (65%) reported acne. Of the 11 women who were born after gestation of 41 weeks or longer, but who weighed 7·5 lb or less, none had hirsutism and only four (36%) had a history of acne.

Women with normal ovaries

We examined the associations between plasma hormone concentrations and birth size and length of gestation among the 186 women with normal ovaries. The trends in plasma LH with length of gestation and birthweight seen among women with polycystic ovaries were not significant, and the trend in plasma testosterone with birthweight was weaker (p=0·05). However, the concentrations of both hormones fell with increasing maternal weight (p=0·03 for LH and 0·02 for testosterone). We found a similar but

Discussion

21% (49) of the 235 women examined had polycystic ovaries. This frequency is similar to that recorded by means of ultrasound in another population study, though the women in that study were younger.³ As expected, women with polycystic ovaries tended to have menstrual irregularities, acne, hirsutism, and higher concentrations of plasma LH and testosterone than women with normal ovaries, and a high ratio of LH to FSH (table 1).1, 2, 3, 4 Because we examined cases from a population sample rather

References (25)

IF Stein et al.
Amenorrhoea associated with bilateral polycystic ovaries
Am J Obstet Gynecol
(1935)
S Franks et al.
Ovulatory disorders in women with polycystic ovary syndrome
Clin Obstet Gynaecol
(1985)
DW Polson et al.
Polycystic ovaries: a common finding in normal women
Lancet
(1988)
RL Rosenfield et al.
Dysregulation of cytochrome P450cl7a as the cause of polycystic ovarian syndrome
Fertil Steril
(1990)
DJP Barker et al.
Weight gain in infancy and cancer of the ovary
Lancet
(1995)
S Franks
Polycystic ovary syndrome
N Engl J Med
(1985)
GA Burghen et al.
Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease
J Clin Endocrinol Metab
(1980)
A Dunaif
Insulin resistance and ovarian dysfunction
GS Conway et al.
Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome
Clin Endocrinol
(1992)
R Pasquali et al.
The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women
Clin Endocrinol (Oxf)
(1993)

SSC Yen et al.

Inappropriate secretion of follicle stimulating hormone and luteinising hormone in polycystic ovarian disease

J Clin Endocrinol Metab

(1970)

GF Erikson et al.

Functional studies of aromatase activity in human granulosa cells from normal and polycystic ovaries

J Clin Endocrinol Metab

(1979)

Cited by (198)

Genetic basis of metabolism and inflammation in PCOS
2023, Human Reproductive and Prenatal Genetics
PCOS is a complex and heterogeneous disorder characterized by hyperandrogenemia, insulin resistance, and chronic anovulation affecting 6%–10% women of childbearing age worldwide. It is the most common endocrine and metabolic disorder in reproductive age women with an enigmatic pathophysiologic and molecular basis. PCOS is a heterogeneous disorder that defined by a combination of signs and symptoms of androgen excess (hirsutism and/or hyperandrogenemia) and ovarian dysfunction (oligo-ovulation and/or polycystic ovarian morphology (PCOM)). Besides, many body systems are affected in PCOS, resulting in several health complications, including menstrual dysfunction, infertility, hirsutism, acne, and metabolic syndrome. Insulin resistance, obesity, hypertension, cardiovascular issues, dyslipidemia, etc., are comorbidities of PCOS. Due to the complex etiology and its heterogeneous nature, the cause of PCOS is unknown, but studies suggest that PCOS might be a complex multigenic disorder with strong epigenetic and environmental influences, including diet and other lifestyle issues. Currently, PCOS is considered a polygenic trait that might result from the interaction of susceptible and protective genomic variants and environmental factors, during either prenatal or postnatal life. Twin studies of heredity provide the most rigorous demonstration that the disorder has genetic components, which showed that genetic influences explain over 70% of PCOS pathogenesis. Recent years, several studies have shown that women with PCOS present with chronic low-grade inflammation and metabolic disorders, indicating that inflammatory factors and metabolites contribute to the development of PCOS. Risk factors causing multiple aberrations in steroidogenesis, folliculogenesis, metabolic pathways and low-grade inflammation are continuously recognized, but the key abnormality escapes detection. In this chapter, we will explore the genetic basis of metabolism and inflammation in PCOS.
Review of the effects of polycystic ovary syndrome on Cognition: Looking beyond the androgen hypothesis
2022, Frontiers in Neuroendocrinology
Polycystic-ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, and many features associated with PCOS – such as elevated androgens, insulin resistance and inflammation – are known to affect cognition. However, effects of PCOS on cognition are not well-understood. Here we review the current literature on PCOS and cognition, note the extent of PCOS symptomatology studied in relation to cognitive outcomes, and identify key research gaps and common methodological concerns. Findings indicate a pattern of worse performance across cognitive domains and brain measures in women with PCOS relative to non-PCOS controls, as well as a lack of evidence for the common assumption that women with PCOS will have higher performance on tasks with a demonstrated male-advantage due to high testosterone levels. We suggest strategies for moving beyond the focus on elevated androgens, in favor of research practices that account for the nuances and heterogeneity of PCOS symptoms.
Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies
2020, Molecular Metabolism
Citation Excerpt :
Thus, girls born from mothers with PCOS might be at a greater risk of developing this endocrine disorder not only due to the abnormal exposure to androgens during gestation, but also due to the intrauterine AMH excess. Low birth weight as a consequence of intrauterine growth restriction has also been proposed as a contributing factor for the development of PCOS [67,68]. In this sense, it has been shown that the prevalence of symptoms of PCOS is higher in young adult women born small for gestational age compared with women with adequate body weight at birth, exhibiting altered insulin sensitivity, increased androgenic activity, and irregular menses [69,70].
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited.
This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions.
Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome.
Anti-Müllerian Hormone in Girls with Premature Adrenarche: The Impact of Polycystic Ovary Syndrome History in their Mothers
2019, Journal of Pediatrics
Citation Excerpt :
However, not all girls with premature adrenarche will be at risk of developing the conditions mentioned herein, and other studies have failed to find a link between premature adrenarche and low birth weight, insulin resistance, or ovarian hyperandrogenism.21,22 Because low birth weight has been linked to altered gonadal function and PCOS23,24 and with increased AMH concentration even in early infancy,25 we recruited only girls born appropriate for gestational age to eliminate the possible influence of low birth weight on AMH serum levels. The increased AMH serum concentration we found in girls with premature adrenarche does not directly show an increased risk of developing PCOS later in life but, at least from the available data in the literature, suggests an increased ovarian follicular pool and altered follicular development.
To assess whether the serum levels of anti-Müllerian hormone (AMH) are increased in girls with premature adrenarche because they are at a higher risk of developing polycystic ovary syndrome (PCOS) later in life.
We measured serum levels of AMH, dehydroepiandrosterone sulfate (DHEAS), testosterone, sex hormone binding globulin, androstenedione, and 17-hyroxyprogesterone in 89 girls with premature adrenarche aged 6.98 ± 1.60 years, and in 55 prepubertal normal girls aged 6.78 ± 1.60 years.
AMH was significantly higher in girls with premature adrenarche (2.95 ± 1.20 ng/mL) compared with normal prepubertal girls (2.00 ± 0.95 ng/mL; P < .001), whereas their body mass index SD score was similar (P > .05). DHEAS, testosterone, and androstenedione were increased in premature adrenarche, whereas sex hormone binding globulin was decreased in girls with premature adrenarche. Among the 89 girls with premature adrenarche, 33 were daughters of mothers with a positive history of PCOS, whereas the mothers of the remaining 56 girls with premature adrenarche had a negative history of PCOS. The girls with a mother with a positive history of PCOS had significantly higher AMH serum levels compared with girls with a mother with a negative history of PCOS (3.37 ± 1.72 ng/mL vs 2.70 ± 1.25 ng/mL; P < .05) with no differences in testosterone, DHEAS, androstenedione, and sex hormone binding globulin. The serum concentration of AMH was only positively related to androstenedione (r = 0.538; P < .0001).
Girls with premature adrenarche, especially those from mothers with a history of PCOS, could have a higher risk of developing PCOS later in life because they have increased serum AMH.
PCOS and Type II Diabetes
2019, Pediatric Type II Diabetes
Polycystic ovary syndrome (PCOS) is a common, multifactorial endocrinopathy. An estimated 5%–20% of young women are afflicted with the syndrome, depending upon the diagnostic criteria used and the ethnic population being studied. This chapter provides information on the diagnosis and treatment of PCOS, with special attention paid to review of our current understanding of the accompanying insulin resistance, metabolic syndrome, and type 2 diabetes in adolescents with the disease.
Assessment of anogenital distance as a diagnostic tool in polycystic ovary syndrome
2018, Reproductive BioMedicine Online
Is anogenital distance (AGD) a useful clinical tool for predicting polycystic ovarian syndrome (PCOS) and its main National Institutes of Health (NIH) phenotypes?
Case–control study conducted between September 2014 and May 2016 at the Department of Obstetrics and Gynecology of the University Clinical Hospital ‘Virgen de la Arrixaca’ in the Murcia region (south-eastern Spain). One hundred and twenty-six cases of PCOS and 159 controls without PCOS were included. AGD measurements were taken from the anterior clitoral surface to the upper verge of the anus (AGD_AC), and from the posterior fourchette to the upper verge of the anus (AGD_AF). Parametric and non-parametric tests and receiver operating characteristic (ROC) curves were used to assess associations between AGD and the presence of PCOS and its phenotypes.
AGD_AC, but not AGD_AF, was associated with PCOS and all its phenotypes (P-values < 0.001 to 0.048). The highest area under the curve (0.62; 95% confidence interval 0.55 to 0.71) was obtained for all PCOS with AGD_AC with a sensitivity and specificity of 50.0% and 73.0%, and positive and negative predictive value of 59.0% and 64.4%, respectively.
AGD_AC could moderately discriminate the presence of PCOS and may be a useful clinical tool.

View all citing articles on Scopus

View full text

ArticlesFetal growth, length of gestation, and polycystic ovaries in adult life

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Mothers' weights

Symptoms

Women with normal ovaries

Discussion

Am J Obstet Gynecol

Clin Obstet Gynaecol

Lancet

Fertil Steril

Lancet

Polycystic ovary syndrome

N Engl J Med

Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease

J Clin Endocrinol Metab

Insulin resistance and ovarian dysfunction

Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome

Clin Endocrinol

The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women

Clin Endocrinol (Oxf)

Inappropriate secretion of follicle stimulating hormone and luteinising hormone in polycystic ovarian disease

J Clin Endocrinol Metab

Functional studies of aromatase activity in human granulosa cells from normal and polycystic ovaries

J Clin Endocrinol Metab

Articles
Fetal growth, length of gestation, and polycystic ovaries in adult life