Role of counselling in infertility

03Feb, 2024

Normal puberty

The term puberty is used to indicate the maturity of the reproductive axis, appearance of secondary sexual characters and the ability to reproduce.

Puberty is a dynamic process which is brought about by a sequence of events resulting in episodic secretions of gonadotropin releasing hormone (GnRH) from the hypothalamus. This process is finely regulated by genetic, neuronal, environmental, and metabolic factors.

The onset of puberty occurs by activation and maturation of HPG (Hypothalamo Pituitary Gonadal)axis, and this can be described in 6 phases.

  1. Fetal: During embryogenesis, the Olfactory placode is the place of origin of the GnRH neurons. These neurons migrate from there to the hypothalamus. The development of the hypothalamo-hypophyseal portal venous system starts by about 6 to 10 weeks of intrauterine life and it is completed by 19 to 20 weeks. In response to pulsatile GnRH secretion, the anterior pituitary starts to produce FSH and LH in fetus by the end of 12 weeks, the secretions peaking by about 20 to 24 weeks before falling over the last 10 weeks. Thus, the HPG axis active in early intrauterine is inactive at birth.
  2. Infancy (phase of mini puberty) Soon after birth , there occurs activation of HPG axis. Gonadotropins and gonadal steroids escalate to maximum levels at around 3-6 months in males and 12-18 months in females. FSH is increased in girls while LH is increased in boys. The cause is speculated to be sudden withdrawal of hormones and escape of the HPG axis from the negative feedback.
  3. Gradual fall in activity of HPG axis: The gonadotropins fall to low levels by 9-12 months in boys and 24-36 months in girls. The reproductive axis is shut down and remains hypoactive until puberty.
  4. Juvenile pause: Between phases of infancy and puberty, known as the juvenile pause, the HPG axis remains dormant. There is erratic, low amplitude GnRH secretion. FSH increases more than LH, but it is not detectable in peripheral blood. The biphasic pattern from birth to puberty is under central control suppression disproving the gonadostat theory.
  5. Reactivation at night - This is the 3rd and final reactivation of the HPG axis which occurs during adolescence. The LH shows a nocturnal rise in early puberty, with increase in amplitude rather than frequency. The peak amplitude of LH rises by about 20 times while that of the FSH rises by twofold.
  6. Puberty - LH begins to rise even during daytime. Increased LH increases estrogen with onset of gonadarche and development of breasts ( thelarche). Sustained increase in the basal estrogen for a year culminates in menarche. However, it takes a year for cycles to become regular.

Factors responsible for puberty include:

  1. Neuroendocrine factors
  2. Genetic factors
  3. Nutritional factors.

Neuroendocrine factors

There exist Central and Peripheral pathways having inhibitory and activator mechanisms.

Central pathway- The inhibitors include GABA (gamma amino butyric acid), Neuropeptide Y (NPY) and MKRN3 ( Macorin ring finger protein 3) Disruption of inhibitor mechanism causes precocious puberty, The central activator mechanisms of neuroendocrinology include Glutamates and Kisspeptins which increase GnRH and promote puberty.

The peripheral signalling mechanisms- Leptin acts as an activator and Ghrelin acts as an inhibitor. Leptin is produced by adipocytes, and it reduces the appetite and increases energy expenditure via decreased expression of NPY gene. It also plays a permissive role by up regulating Kisspeptins. Ghrelin is a gut hormone, also secreted in the brain and inhibits GnRH secretion.

Genetic factors controlling puberty

Kiss-1 gene is one of the genes that is involved in the expression at puberty and is present on the long arm of chromosome 1. Epigenetic mechanisms influence the pubertal onset. The beginning of puberty parallels maturation of Kisspeptin neurons. The KNDY neurons- Kisspeptin, Neurokinin and Dynorphin neurons-are present in the preoptic and infundibular region of the hypothalamus. The axons of these neurons end on the GnRH producing neurons. This group regulates itself via autocrine activity. The Neurokinin-B neurons are stimulatory while the Dynorphin are suppressant.

Arousal of kisspeptin system at puberty causes regular pulsatile secretion of GnRH which results in the release of LH predominantly and thus the HPG axis is reactivated.

Mutation of Kiss-1R (Kiss-1receptor) gene or Kiss-1gene can cause loss of function and result in hypogonadotropic-hypogonadism(HH) which results in absent pubertal development. Activating mutations in Kiss-1R or Kiss-1 gene can cause precocious puberty. Kisspeptin neurons have estrogen and progesterone receptors which the GnRH secreting neurons lack. Hence all the feedback from the peripheral steroid hormones is through the Kisspeptin neurons. The excitatory and inhibitory feedback are therefore mediated through the kisspeptin neurons.

Nutritional factors in onset of puberty

There is a global trend in earlier onset of puberty in girls than in previous centuries. Body fat of around 17% triggers puberty and increased body fat means earlier puberty.

Relationship between obesity and early puberty

  1. Increase in the weight leads to increased leptin levels which in turn induces kisspeptin release.
  2. Increase in IGF-1 ( Insulin like growth factor) causes reduced SHBG ( Sex Hormone Binding Globulin) and hence increased bioavailability of sex steroids.

However, the relationship between obesity and early puberty in boys is not clear.

It is believed that an increase in the animal protein intake like the dairy products which may have increased IGF-1 and increased micronutrients and fatty acids may all cause earlier sexual maturation.

EDCs (Endocrine disrupting factors)

EDCs act via multiple mechanisms. Polychlorinated biphenyls in fish from adulterated water, Lead, Bisphenol A, plant derived phytoestrogens in packing are some EDCs which have been implicated as disrupting the endocrine milieu and causing early breast development and accelerated puberty.

Stages of pubertal development

The sequence and tempo of puberty varies in children. 50 to 80% of it is accounted for by genetic factors. Maternal and paternal pubertal timing correlates with the timing in children. Other determining factors include genetics, gender, nutrition, race, physical inactivity, and co-morbidities. Adrenarche is the activation of the adrenal cortex and occurs independent of puberty. The adrenal zona reticularis is responsible for secretion of adrenal androgens, resulting in an increase in DHEA/DHEAS and androstenedione. Clinically this stimulates the development of axillary and pubic hair. Pubarche occurs around 11 years of age.

Gonadarche-This is the activation of gonads resulting in steroid secretion and initiation of gametogenesis. Clinically it is manifest as Thelarche and menarche. Thelarche occurs on an average between 10-11 years and menarche around 12.5 years.

Puberty in girls

Adrenarche occurs around 6 years of age and the HPO axis is activated 2-3 years later. DHEAS levels over 40mcg/dl is a biochemical indicator of adrenarche.

Pubertal growth spurt contributes to 15 to 20% of the adult growth. Accelerated height is the first sign of pubertal onset in girls. Increase in height and weight begins around 9-10 years in girls and 11-12 years in boys.

Estrogen enhances growth hormone (GH) levels early in puberty.GH stimulates the secretion of IGF-1 from liver and the epiphyseal plate. This causes chondrogenesis at the epiphyseal plates resulting in growth of long bones and increase in height. Prolonged exposure to estrogen leads to epiphyseal plate closure and halts the height.

Bone age and skeletal age is assessed by X ray of the left wrist and interpreted with Bayley-Pinneau tables and Greulich Pyle Atlas. Normally bone age should correspond to chronological age. In Delayed puberty, the bone age is delayed while in precocious puberty the bone age is accelerated.

Puberty in boys

The first sign is growth and enlargement of testis. (Tanner stage 2, testicular length over 2.5 cms or volume more than 4 ml). 2 years later there is the development of pubic hair and another 2 years later there is the development of axillary hair. Increased testosterone causes voice cracking and increased muscle mass. Testosterone is converted to dihydrotestosterone by the action of the enzyme 5 alpha reductase. Dihydrotestosterone causes growth of the penis and the scrotum, enlargement of the prostate, appearance of pubic and facial hair, and temporal hairline recession. Growth spurt is initiated when the testicular volume is about 10-12 ml. Peak height velocity for boys occurs around 13 to 14 years.

Normal variants of puberty

Pubertas tarda - This is a constitutional delay where puberty starts over 2 standard deviations later than mean age of onset of puberty.

Constitutional acceleration - Puberty starts over 2 standard deviations earlier than the mean age of onset but not before 8 years in girls and 9 years in boys.

Premature thelarche - This is isolated breast development without any other abnormal development. This is often because of exposure to EDCs. However, these cases have to be followed up every 6 months in order to rule out Central precocious puberty.

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